RU2743637C2 - Pharmaceutical composition containing one or more esters of fumaric acid in a decomposable matrix - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: group of inventions relates to pharmaceutical compositions of fumaric acid esters. Pharmaceutical composition in form of a tablet with a degradable matrix contains core containing 35–55 % by weight of a dimethyl fumarate nucleus; 3–6 wt % hydroxypropyl cellulose core; 40–60 % by weight of lactose nucleus; 0.15–0.7 % by weight of magnesium stearate nucleus and 0.05–0.25 % by weight of silicon dioxide core; and an enteric coating which is applied at 1.5–3.5 % by weight of the core. Also disclosed is a method of treating and using a pharmaceutical composition for treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, Crohn's disease, nonspecific ulcerative colitis, polyarthritis, multiple sclerosis, juvenile sugar diabetes, Hashimoto thyroiditis, Graves' disease, systemic lupus erythematosus, Sjogren's syndrome, pernicious anemia, chronic active (lupous) hepatitis, rheumatoid arthritis, lupus nephritis, pemphigus, scleroderma, organ transplant rejection, myasthenia gravis, uveitis, refractory uveitis, spring conjunctivitis or optic neuritis and other diseases.EFFECT: group of inventions provides controlled release of fumaric acid esters.19 cl, 2 dwg, 2 tbl, 43 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a pharmaceutical formulation containing a degradable matrix. In particular, the present invention relates to a pharmaceutical formulation comprising an erodible matrix containing one or more fumaric acid esters as well as one or more rate control agents, wherein the decomposition of said degradable matrix provides for a controlled or sustained release of said fumaric acid esters.

LEVEL OF TECHNOLOGY

Psoriasis is a chronic skin disease with a high percentage of genetic predisposition. This disease varies from exacerbation to periods of complete calm. Patients with psoriasis can have severe physical disabilities due to the external characteristics of the disease. It affects all areas of life, such as professional careers as well as personal and private life.

The treatment options available prior to treatment according to the present invention are limited, in particular, for patients with moderate to severe psoriasis, and many provide only temporary and short-term improvement and / or have severe adverse effects / side effects. Because psoriasis has a high relapse rate, most patients should receive long-term treatment.

Fumaric acid esters have been used to treat moderate to severe psoriasis for over 30 years. In 1994, Germany approved a specific mixture of dimethyl fumarate and monoethyl fumarate salts - Fumaderm® initial / Fumaderm® (Fumaderm® initial / Fumaderm®). One Fumaderma® enteric coated tablet contains the following active ingredients: dimethyl fumarate 120 mg; ethyl hydrofumarate, calcium salt 87 mg; ethyl hydrofumarate, magnesium salt 5 mg; ethyl hydrofumarate, zinc salt 3 mg and the following other components: croscarmellose sodium, talc, magnesium stearate, dyes E 171 and E 132, copolymer of methacrylic acid and methyl methacrylate (1: 1), copolymer of methacrylic acid and ethyl acrylate (1: 1), Macrogol 6000 (Macrogol 6000), simethicone, povidone, triethyl citrate, microcrystalline cellulose, highly dispersed silica [Fumaderm® Drug Summary, January 2009 version]. Today Fumaderm® represents approximately 66% of all systemic psoriasis prescriptions in Germany. However, the high incidence of side effects is the reason why some patients stop taking at the beginning of treatment. It is believed that gastrointestinal side effects and hyperemia can, at least in part, be attributed to the release properties of the prescribed formulation resulting in high local concentrations in the intestine.

The present inventors contemplate that an improvement in the treatment regimen can be achieved by administering a pharmaceutical composition designed to deliver the active substance in a controlled manner, i.e. in a manner that is prolonged, delayed, delayed, slow and / or delayed as compared to delivery of a commercially available product.

Fumaric acid esters such as dimethyl fumarate can be subject to degradation and hydrolysis. For example, it is known that dimethyl fumarate is more susceptible to hydrolysis in alkaline / less acidic media than in more acidic media (litjens et al, "In vitro pharmacokinetics of anti-psoriatic fumaric acid esters", BMC Pharmacology 2004, 4:22). Thus, it is believed that dimethyl fumarate is more susceptible to hydrolysis in the small intestine than in the stomach. In addition to the effect of pH described above, esterase is believed to aid in the hydrolysis of fumaric acid esters.

WO 2006/037342 describes controlled release pharmaceutical compositions containing fumaric acid ester (es) as active substance (s), the controlled release characteristics resulting in a reduction in gastrointestinal (gastrointestinal) side effects.

OBJECT OF THE INVENTION

The object of the embodiments of the present invention is to provide a controlled or sustained release pharmaceutical composition containing fumaric acid ester (es) as active substance (s), which exhibits reduced side effects associated with the gastrointestinal tract (gastrointestinal tract), and / or reduced hyperemia compared to the Fumaderm® formulation known from the prior art. Another object of the present invention is to provide a controlled or sustained release pharmaceutical formulation containing fumaric acid ester (es) as active substance (s), which has an improved pharmacokinetic profile compared to formulations known in the art. In particular, it is an object of the present invention to provide a controlled or sustained release pharmaceutical formulation containing fumaric acid ester (es) as active substance (s) that exhibits reduced AUC variability (AUC) and / or C _max values compared to formulations with controlled release, known in the art. In particular, it is an object of the present invention to provide a controlled or sustained release pharmaceutical formulation containing fumaric acid ester (es) as active substance (s), which demonstrates sufficient relative bioavailability compared, for example, to the Fumaderm® formulation known from the prior art. ... Specifically, it is an object of the present invention to provide a controlled or sustained release pharmaceutical formulation containing fumaric acid ester (es) as active substance (s) that exhibits reduced AUC variability and / or C _max values compared to the prior art Fumaderm® formulation. technology.

BRIEF DESCRIPTION OF THE INVENTION

The present inventors have found that controlled or sustained release of one or more fumaric acid esters can be achieved by means of a tablet with a degradable matrix. The prolongation of the release of the active pharmaceutical ingredient (API) can be controlled by the amount of rate-controlling polymer (s) relative to the other components, and it is believed that high local API concentrations can be avoided or reduced.

It has been found that a controlled or sustained release of one or more fumaric acid esters at pharmaceutically appropriate levels can be achieved, compared to Fumaderm®, from a small tablet to improve patient compliance and treatment, while high local API concentrations can be avoided when ensuring the most complete delivery of the active substance within a certain period of time after reaching the site of absorption, and at the same time, reduced variability compared to Fumaderm® can be provided.

It was found that the compositions according to the present invention show a good correlation in vitro / in vivo. In one aspect, the in vitro / in vivo correlation is determined by comparing the time to release 80% of the fumaric acid ester from the formulations in an in vitro dissolution test with the C _max measured in vivo after the formulations are administered.

The inventors also contemplate that controlled release of the API by matrix erosion minimizes or reduces the exposure of the API to hydrolysis in the gastrointestinal tract, thereby reducing the degradation of the API prior to absorption.

In accordance with the first aspect, it is believed that in this way it is possible to maintain the effect of the treatment and at the same time significantly reduce some or some of the unwanted side effects or negative effects known for Fumaderma® or improve tolerance compared to Fumaderm®.

In accordance with another aspect, it is believed that in this way it is possible to achieve an improved treatment effect compared to Fumaderm® and at the same time reduce the undesirable side effects known to occur in the treatment of psoriasis with said prior art Fumaderm®.

In accordance with another aspect, it is believed that in this way it is possible to achieve an improved treatment effect while maintaining tolerance as compared to Fumaderm®.

In accordance with another aspect, it is believed that in this way it is possible to achieve an improved treatment effect while improving tolerance in comparison with Fumaderm®.

According to a first aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

i) from 10 wt.% to 80 wt.% one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance; and

ii) 1-50 wt% of one or more rate control agents;

the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

i) from 30 wt.% to 60 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance; and

ii) 3-40 wt% of one or more rate control agents; the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

i) from 10 wt.% to 80 wt.% one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance; and

ii) 1-50 wt% of one or more rate control agents;

the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

i) from 30 wt.% to 60 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance; and

ii) 3-40 wt% of one or more rate control agents;

the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

A) tablet core containing:

i) 40-60 wt.% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 4-6 wt% rate control agent;

iii) 35-55 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

A) tablet core containing:

i) 40-60 wt.% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 4-6 wt% rate control agent;

iii) 35-55 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a degradable matrix tablet, comprising:

A) tablet core containing:

i) 30-60 wt.% dimethyl fumarate,

ii) 3-6 wt% hydroxypropyl cellulose;

iii) 35-65 wt% lactose;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of dimethyl fumarate - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6 , 8 as a dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of dimethyl fumarate contained in the specified composition is released.

In accordance with one aspect, the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, comprising:

A) tablet core containing:

i) 30-60 wt.% dimethyl fumarate,

ii) 3-6 wt% hydroxypropyl cellulose;

iii) 35-65 wt% lactose;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of dimethyl fumarate - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6 , 8 as a dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of dimethyl fumarate contained in the specified composition is released.

In the present context, the term "wt%" refers to the percentage by weight of each component in the tablet core, thus excluding any outer coatings or films.

In accordance with another aspect, the present invention relates to a method for preparing a composition according to the present invention, comprising the following steps:

a) Dissolving or suspending either one or both the fumaric acid ester and the rate controlling agent in the form of a polymeric matrix material in water to form an aqueous suspension of said materials;

b) Applying said aqueous suspension by spraying onto the fumaric acid ester and / or binder granules for a period of time sufficient to obtain a uniform coating thereon;

c) Drying the resulting granules;

d) Screening or grinding of said granules is possible;

e) Preparing a mixture with any pharmaceutically acceptable excipients and additives in a manner known per se to form a tablet formulation;

f) Optionally, film coating or enteric coating of said tablet formulation in a manner known per se;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C.

It is known that, for example, dimethyl fumarate can be lost during sublimation, and sublimation is more pronounced at higher temperatures.

In accordance with some aspects, the manufacture of the compositions of the present invention is carried out at a relatively low temperature to minimize or reduce sublimation, and includes multiple intermediate steps and minimal non-mechanized steps. These factors contribute to the manufacturing process being scalable and feasible in an industrial setting and on an industrial scale. In accordance with some aspects, it has been found that the compositions of the present invention can be made on a larger scale, such as at least 15 kg, such as at least 20 kg, such as at least 30 kg.

In accordance with another aspect, the present invention relates to a method for preparing a composition according to the present invention, comprising the following steps:

a) Dissolving or suspending the rate controlling agent in the form of a polymeric matrix material in water to form an aqueous suspension of said material;

b) Applying the specified aqueous suspension by spraying onto the fumaric acid ester granules for a period of time sufficient to obtain a uniform coating thereon;

c) Drying the resulting granules;

d) Screening or grinding of said granules is possible;

e) Preparing a mixture with any pharmaceutically acceptable excipients and additives in a manner known per se to form a tablet formulation;

f) Optionally, film coating or enteric coating of said tablet formulation in a manner known per se;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C.

In accordance with another aspect, the present invention relates to a method for preparing a composition according to the present invention, comprising the following steps:

a) Screening or crushing of fumaric acid ester crystals is possible;

b) Blending said crystals of fumaric acid ester, a rate controlling agent in the form of a polymeric matrix material, and any pharmaceutically acceptable excipients and additives by direct compression to form a tablet formulation;

c) It is possible to film and / or enteric coatings on said tablet formulation in a manner known per se;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C.

In accordance with another aspect, the pharmaceutical composition of the present invention is intended for use in the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, sclerotherapy, pemphigus vulgaris nerve pain, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplants (prevention of rejection), sarcoidosis, necrobiosis lipoidosis, or anular granuloma.

Another aspect of the present invention is the use of a pharmaceutical composition according to the present invention for the preparation of a medicament for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uvectivitis, vernal sclerosus , optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidosis, or anular granuloma.

Another aspect of the present invention is a method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic red lupus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, neuritis, optic nerve pain pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, lipoid necrobiosis or anular granuloma, said method comprising oral administration to a patient in need of an effective dose of a pharmaceutical composition according to of the present invention.

EXPLANATION TO DRAWINGS

FIG. 1 shows the in vitro dissolution characteristics at 37 ° C using a dissolution paddle apparatus at 100 rpm using 0.1 N hydrochloric acid as dissolution medium for the first 2 hours of the test followed by 0.05 M phosphate buffer. with a pH of 6.8 as dissolution medium for the remaining test period of the film-coated or enteric-coated tablets with the degradable matrix of the present invention, as described in Examples 16, 18, 20 and 22.

FIG. 2 shows the in vitro dissolution characteristics at 37 ° C using a dissolution paddle at 100 rpm using 0.1 N hydrochloric acid as dissolution medium for the first 2 hours of the test followed by 0.05 M phosphate buffer. with a pH of 6.8 as dissolution medium for the remaining test period of the film-coated degradable matrix tablet of the present invention, as described in Example 23.

DETAILED DESCRIPTION OF THE INVENTION

In the present context, the term "API", which is an abbreviation for "active pharmaceutical ingredient", and the term "active ingredient" are interchangeable and refer to the fumaric acid ester (es) to be released from the pharmaceutical composition of the present invention.

In the present context, the term "controlled or sustained release" refers to release from a formulation designed to release the fumaric acid ester in a prolonged, retarded, slow and / or delayed manner compared to the release of the commercially available Fumaderm® product when tested under comparable conditions (for example, for in vivo studies: dose equivalents with or without standardized food, etc., or for in vitro studies: dose equivalents, a dissolution test device and conditions including, for example, the composition, volume and temperature of the dissolution medium used, rotation speed, etc.).

The in vivo release can be tested by measuring the plasma concentration at predetermined times and thus by obtaining a plasma concentration versus time plot for the fumaric acid ester or metabolite thereof, if appropriate. In addition, it is assumed that metabolism occurs already in the gastrointestinal tract or during the passage of the mucous membrane of the gastrointestinal tract, or during the first passage through the hepatic circulation. Accordingly, when dimethyl fumarate is administered, the appropriate component for detection in plasma may be monomethyl ester rather than fumaric dimethyl ester.

Other assays can also be used to determine or measure the in vivo release of an active substance. Thus, animals (eg dwarf pigs, dogs, etc.) can be used as a model. These animals receive the test compositions and after certain periods of time take blood samples and determine the content of the active component (or its metabolite, if necessary) in the plasma or specific organs, or extracted from the intestinal contents.

Another test involves the use of a specific segment of the intestine of an animal or human. The segment is placed in a suitable device containing two chambers (donor and recipient) separated by the segment, and the test composition is placed in a suitable medium in one chamber (donor chamber). The composition will release the active agent, which is then transported across the intestinal segment. Accordingly, at suitable intervals, the concentration of the active substance (or, if appropriate, metabolite) is measured in the receiving chamber.

A person skilled in the art will be able to apply the above method to a particular composition.

Regarding in vitro methods, known methods are available, in particular those described in official monographs such as, for example, the United States Pharmacopoeia (USP) or the European Pharmacopoeia. The person skilled in the art knows which method to select and how to select the specific conditions for performing an in vitro test. For example, the USP prescribes in vitro tests at 37 +/- 1.0, for example 37 +/- 0.5 degrees Celsius / centigrade. In one aspect, a suitable dissolution test is a test in which dissolution characteristics are determined as described in the United States Pharmacopoeia at 37 ° C using a dissolution paddle apparatus at 100 rpm using 0.1 N hydrochloric acid in as the dissolution medium for the first 2 hours of the test, and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium for the remainder of the test period. The person skilled in the art knows how to adjust the applied conditions, for example, temperature, pH, paddle speed, duration, etc. In another aspect, in vitro dissolution testing is performed as follows: USP instrument II (paddles) with 1 liter vessels are used. The bath temperature is set at 37 ° C ± 0.5 ° C and the blade speed at 100 rpm. One tablet is placed in one vessel containing 750 ml of 0.1 N HCl (pH 1.2) for 2 hours. The pH is then changed to 6.8 by adding 220 ml of 0.2 M sodium phosphate buffer. Samples of 1.5 ml were taken at each sampling time point and analyzed by HPLC on DMF. HPLC parameters were set as follows: Column: Phenomenex Luna C18, 50 x 4.6 mm, 3 μm; column oven temperature 30 ° C,: mobile phase: Methanol: 20 mM phosphate buffer pH 3.0 (35:65 v / v), injected volume: 5 μl, flow rate: 0.8 ml / min, wavelength detector: 210 nm, chromatography time 5 minutes, retention time of DMF 3.5 minutes.

In the present context, the term "relative bioavailability" refers to the comparison of the amount of drug absorbed (expressed as area under the curve (AUC)) following the administration of two different formulations or a reference product. In the present context, the amount of absorbed drug, expressed as AUC, can be detected in the form of the actual drug administered or its metabolite. The relative bioavailability can be expressed as a percentage of the reference AUC, i.e. % PPK.

In the present context, the term "variability" refers to the variability of PK parameters (eg, C _max and AUC) after administration of a pharmaceutical formulation or reference formulation. Variability can be expressed as the coefficient of variation (CV) for the PK parameter, i.e. ratio of standard deviation and mean.

In the present context, the term "tolerance" refers to the effect of a drug that is tolerated by subjects and / or patients. In one aspect, "tolerance" is defined as the effect of a drug tolerated by subjects and / or patients in the early stages of treatment, for example, during the first three months after starting treatment, for example, during the first month after starting treatment, for example, in during the first two weeks after starting treatment, for example, during the first week after starting treatment, for example, during the first three days after starting treatment, for example, during the first day after starting treatment, for example, after the first dose of treatment. A drug that is better tolerated has fewer side effects in the subject and / or patient than a drug that is poorer.

In the present context, the term "substantially absence" refers to a level of less than about 1%, such as less than about 0.5%, such as less than about 0.3%, such as about 0.0%.

In the present context, the terms “rate controlling agent” and “rate controlling agent in the form of a polymeric matrix material” are used interchangeably and refer to an agent that can delay / slow down and / or prolong the release of an active agent in vivo and / or in vitro.

As indicated above, the in vivo and / or in vitro release of the active substance is prolonged, slow and / or delayed compared to the commercially available Fumaderma® composition. In the present context, the term "prolonged" means that the active substance is released over a longer period of time than Fumaderm®, for example, at least over a period of time that is at least 1.2 times, such as, for example, at least at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times more than Fumaderma®. Thus, if, for example, 100% dimethyl fumarate is released from the Fumaderma® tablets 3 hours after the start of the suitable test, then 100% of the dimethyl fumarate in the composition according to the present invention is released at least 3.6 hours after the start of the suitable test.

In the present context, the term "delayed" means that the release of the active substance begins at a later point in time compared to Fumaderm® (for example, after 30 minutes or later, such as 45 minutes or later, 1 hour or later, or 1.5 hours or later).

In the present context, the term "monolithic" refers to one-unit or one-unit.

The composition of the present invention is expected to provide improved tolerability such as fewer and / or less severe gastrointestinal (GI) side effects such as fewer and / or less severe redness such as fewer and / or less severe cases of flushing.

According to the present invention, gastrointestinal (GI) side effect may include, but is not limited to, diarrhea, stomach pain, abdominal pain, abdominal cramps, nausea, bloating, tenesmus, flatulence, increased stool frequency, feeling of fullness and upper abdominal cramps.

In the present context, a decrease in gastrointestinal side effects means a decrease in the severity and / or frequency of occurrence among a given group of patients to be treated when comparing the gastrointestinal side effects observed after administration of the composition according to the present invention with the gastrointestinal side effects observed after administration of Fumaderma®. ... Thus, a reduction in gastrointestinal side effects as defined by this definition can be considered a significant reduction in the incidence of any of the gastrointestinal side effects listed above, such as at least a 10% decrease in the incidence, or more preferably at least a 20% decrease in the incidence. occurrence or even more preferably more than 30% reduction in the frequency of occurrence. A reduction in GI-related side effects can also be expressed as a significant reduction in the severity of any of the GI side effects listed above, such as a decrease in the severity and / or frequency of diarrhea, stomach pain, abdominal pain, abdominal cramps, nausea, bloating, tenesmus, flatulence, increased stool frequency, feeling of fullness or cramps in the upper abdomen. A reduction in the gastrointestinal side effects described above can be observed in a clinical trial setting, either by comparing the administration of a formulation according to the present invention directly with Fumaderm® or with a placebo. In a placebo-controlled study, the incidence of gastrointestinal side effects in patients receiving a formulation of the present invention compared with a placebo group can be compared with previous studies comparing Fumaderm® with placebo (see, for example, Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference: Altmeyer PJ et al, Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad. Dermatol. 1994; 30: 977-81 ).

In accordance with another aspect, the composition according to the present invention - when administered orally and compared to that obtained after oral administration of Fumaderma® tablets in an equivalent dose - reduces gastrointestinal side effects (frequency and / or severity).

In one embodiment, said clinical study can be conducted as described below under the heading "Clinical Study in Patients". In another embodiment, the specified clinical study can be carried out as described below under the heading "Clinical study in healthy volunteers."

Patient Clinical Study: Typically, this study includes patients suffering from psoriasis, and typically more than 10% of the body surface area will be affected by psoriasis (severe psoriasis). However, patients in whom 2 to 10 percent of their body surface area is affected (moderate psoriasis) may also be included. Patients can also be selected based on the Psoriasis Coverage and Severity Index (PASI) score. Typically, patients are included within a specified PASI range, such as 10 to 40, or such as 12 to 30, or such as 15 to 25. In another embodiment, patients with a specified minimum PASI, such as A PASI of at least 8, such as at least 10, such as at least 12, such as at least 15. Patients with any type of psoriasis (chronic plaque type, exanthemic teardrop type, pustular type, psoriatic erythroderma or palmar-plantar type), but in some cases only include patients with a chronic plaque type. In most cases, about 15 to 20 patients in each treatment group (formulation according to the present invention, Fumaderm® or placebo) is sufficient, but more preferably about 30 to 50 patients are included in each study group. The total duration of the study can be from one day to one week, but more preferably the study will be from 8 weeks to 12 weeks, or up to 16 weeks or longer. Side effects can, for example, be estimated as the total number of times a specific side effect was reported in each group (regardless of how many patients experienced the specified side effect), or side effects could be estimated as the number of patients who experienced a specific side effect a certain number of times, for example, at least once, or at least twice, or at least three times during the duration of the study. In addition, the severity of the side effect can be observed, or a certain severity of the side effect may be necessary to classify it as a side effect in the study. A convenient way to assess the severity of side effects is to use a visual analogue scale (VAS).

Clinical study in healthy volunteers: This study will generally be a single-center study after an open, randomized, "inverted" design to study plasma concentrations, pharmacokinetics, safety and tolerability of pharmaceutical formulations of the present invention, possibly using the market formulation of Fumaderm® as a reference. This study can be carried out as detailed in Example 25 below.

In accordance with another aspect, the composition according to the present invention - when administered orally and compared with that obtained after oral administration of Fumaderma® tablets at an equivalent dose - reduces hyperemia (frequency and / or severity).

In the present context, the term "flushing" describes episodic bouts of redness of the skin along with a sensation of warmth or burning sensation of the face and / or neck, and less commonly the upper body and abdomen or the entire body. It is the short-term nature of these attacks that distinguishes hyperemia from constant erythema of photosensitivity or acute reactions to contact. Repeated hyperemia over a long period of time can lead to telangiectasia and sometimes to classic rosacea of the face (Greaves MW. Flushing and flushing syndromes, rosacea and perioral dermatitis. B: Champion RH, et al, eds. Rook / Wilkinson / Ebling textbook of dermatology, 6th ed., Vol. 3. Oxford, UK: Blackwell Scientific, 1998: 2099-2104).

In the present context, a decrease in hyperemia means a decrease in the severity and / or incidence / incidence of hyperemia among a given group of patients to be treated, observed after administration of a formulation according to the present invention, compared with hyperemia observed after administration of Fumaderm®, and can be measured, for example, as described O'toole et al. Cancer 2000, 88 (4): p. 770-776. Thus, a decrease in hyperemia according to this definition can be considered as a decrease in the frequency and / or severity of hyperemia. In accordance with one aspect of the present invention, the incidence of flushing is reduced by at least about a quarter, in accordance with another aspect of the present invention, the incidence of occurrence is reduced by at least about a third, in accordance with another aspect of the present invention, the incidence of occurrence is reduced by at least about by half, and in accordance with another aspect of the present invention, the incidence of flushing is reduced by about two-thirds or more. Likewise, severity in accordance with one aspect of the present invention is reduced by at least about a quarter, in accordance with another aspect of the present invention by at least about a third, in accordance with another aspect of the present invention by at least about half and in accordance with with another aspect of the present invention, at least about two thirds. A 100% reduction in the incidence and severity of flushing is most preferred, but not necessary. The reduction in hyperemia described above can be observed under the conditions of a clinical study, for example, by comparing the administration of a compound according to the present invention, for example, with the administration of Fumaderma®. In the case of a Fumaderm®-controlled study, the incidence and severity, defined as mild, moderate or severe, of flushing in patients receiving a compound of the present invention compared to the Fumaderm® group can be compared.

In accordance with one aspect, the severity of hyperemia is defined as the area of the affected body surface.

In one embodiment, the specified clinical study can be conducted as described above under the heading "Clinical study in patients". In another embodiment, the specified clinical study can be carried out as described above under the heading "Clinical study in healthy volunteers."

In accordance with another aspect, the composition according to the present invention - when administered orally and compared with that obtained after oral administration of Fumaderma® tablets at an equivalent dose - reduces redness (frequency and / or severity).

In the present context, the term "erythema" describes episodic bouts of redness of the skin. According to one aspect, redness occurs on the face, neck and less often in the upper body and abdomen.

In the present context, a reduction in redness means a decrease in the severity and / or frequency of occurrence / frequency of redness among a given curable group of patients observed after administration of the composition according to the present invention, compared to the redness observed after administration of Fumaderma®, and can be assessed, for example, by a physician a clinician or nurse. Thus, a reduction in redness according to this definition can be considered as a decrease in the incidence and / or severity of redness. In accordance with one aspect of the present invention, the incidence of redness is reduced by at least about a quarter, in accordance with another aspect of the present invention, the incidence of occurrence is reduced by at least about a third, in accordance with another aspect of the present invention, the incidence is reduced by at least about by half, and in accordance with another aspect of the present invention, the incidence of redness is reduced by about two-thirds or more. Likewise, severity in accordance with one aspect of the present invention is reduced by at least about a quarter, in accordance with another aspect of the present invention by at least about a third, in accordance with another aspect of the present invention by at least about half and in accordance with with another aspect of the present invention, at least about two thirds. A 100% reduction in the incidence and severity of redness is most preferred, but not necessary. The reduction in erythema described above can be observed under the conditions of a clinical study, for example, by comparing the administration of a compound of the present invention, for example, with the administration of Fumaderma®. In the case of a Fumaderm® controlled study, the incidence and severity, defined as mild, moderate or severe, of redness in patients receiving a compound of the present invention compared to the Fumaderm® group can be compared.

In one aspect, the severity of redness is defined as the area of the affected body surface.

In one embodiment, the specified clinical study can be conducted as described above under the heading "Clinical study in patients". In another embodiment, the specified clinical study can be carried out as described above under the heading "Clinical study in healthy volunteers."

In one embodiment, the relative bioavailability of the composition of the present invention compared to Fumaderm® is at least about 75%, for example at least about 80%, for example at least about 85%, for example at least about 90% , for example, at least about 95%, for example, about 100%.

In one embodiment, the relative bioavailability of the composition of the present invention as compared to Fumaderm® is at least about 100%, for example at least about 110%, for example at least about 120%, for example at least about 125% for example, at least about 130%.

In one embodiment, the relative bioavailability of the composition of the present invention as compared to Fumaderm® is not more than about 130%, for example, not more than about 125%, for example, not more than about 120%, for example, not more than about 110%, for example, not more than about 100%.

In the present context, the term "degradable matrix" refers to a matrix in which the release of the API is not dependent on internal diffusion processes, but rather is the result of the rate of erosion of said matrix. By stripping the eroded layers of the matrix in a well controlled manner, predetermined amounts of API will be obtained, with the release of the API dependent on the rate of swelling and dissolution or erosion of the matrix and on the rate of dissolution, solubility and diffusion rate of the API.

In accordance with one aspect, the present invention relates to a pharmaceutical formulation comprising a degradable matrix that contains:

i) from 10 wt.% to 80 wt.%, for example from 20 wt.% to 70 wt.%, for example from 20 wt.% to 60 wt.%, for example from 30 wt.% to 60 wt. %, for example from 35 wt.% to 60 wt.%, for example, from 35 wt.% to 55 wt.%, for example, from 40 wt.% to 55 wt.%, for example, from 44 wt.% to 55 wt%, for example 40 wt% to 50 wt%, for example 42 wt% to 48 wt% one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl fumaric acid esters and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as an active substance; and

ii) 1 wt% to 50 wt% of one or more rate control agents; the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In accordance with one aspect, the present invention relates to a pharmaceutical formulation comprising a degradable matrix that contains:

i) from 30 wt.% to 60 wt.%, for example from 35 wt.% to 60 wt.%, for example from 35 wt.% to 55 wt.%, for example from 40 wt.% to 55 wt. %, for example, from 40 wt.% to 50 wt.%, for example, from 44 wt.% to 55 wt.%, for example, from 42 wt.% to 48 wt.% of one or more fumaric acid esters selected from di - (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance; and

ii) 3 wt% to 40 wt% of one or more rate control agents; the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

In some embodiments of the present invention, it has been found that it is possible to achieve sustained release with a relatively low amount of rate-controlling agent and at the same time still obtain sufficient drug exposure in a narrow absorption window in the small intestine and thus provide favorable pharmacokinetic properties, such as a sufficient relative bioavailability in comparison, for example, with the Fumaderm® formulation known in the art.

In some additional embodiments, it has been found that it is possible to obtain enteric coated sustained release formulations of the present invention and at the same time obtain sufficient drug exposure in a narrow absorption window in the small intestine and thus provide favorable pharmacokinetic properties. such as sufficient relative bioavailability in comparison, for example, with the Fumaderm® formulation known in the art.

In accordance with one aspect of the present invention, the rate controlling agent is a water-soluble polymer.

As used herein, the term "water-soluble polymer" means a conventional polymer for pharmaceutical use having a solubility of more than 10 mg / ml in water. Suitable water-soluble polymers include, but are not limited to, for example, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose. In one aspect, the water-soluble polymer is hydroxypropyl cellulose.

As used herein, the term "water-soluble polymer" means a conventional polymer for pharmaceutical use having a solubility of not more than 10 mg / ml in water.

In accordance with another aspect of the present invention, the degradable matrix is substantially free of water-insoluble polymer. In another aspect, the degradable matrix does not contain a water-insoluble polymer.

In the present context, the term "substantially not" refers to a level of less than about 1%, such as less than about 0.5%, such as less than about 0.3%, such as about 0.0%.

In accordance with one aspect of the present invention, the rate controlling agent is a water-soluble polymer, and the degradable matrix is substantially free of water-insoluble polymer.

In accordance with one aspect of the present invention, the rate controlling agent is a water-soluble polymer and the degradable matrix does not contain a water-insoluble polymer.

In one embodiment, the rate controlling agent is a cellulosic polymer or cellulose derivative, or a mixture of these. As non-limiting examples of the cellulosic polymer or cellulose derivative, or mixtures of these substances, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, and mixtures of these substances can be mentioned.

In one embodiment, the rate controlling agent is hydroxypropyl cellulose. There are many different grades of hydroxypropyl cellulose depending on, for example, its molecular weight, degree of esterification, viscosity, etc. Non-limiting typical versions of commercially available hydroxypropyl celluloses can be obtained, for example, from Aqualon or Nippon Soda under the trade names Klucel® HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-N, etc. In one embodiment, the rate controlling agent is hydroxypropyl cellulose having a viscosity (mP) of 3.0-5.9 measured in an aqueous solution containing 2 wt% dry HPC at 20 ° C. In one embodiment of the present invention, the rate controlling agent is HPC-SL.

In one embodiment, the rate controlling agent is present in an amount of 1-40 wt%, for example, about 3-35 wt%, for example, about 4-15 wt%, for example, about 4-10 wt%. %, for example, about 3-15 wt.%, for example, about 3-10 wt.%, for example, about 3-6 wt.%, for example, about 3-5.5 wt.%, for example, about 4-6 mass%.

In one embodiment, the rate controlling agent is present in an amount of 1-40 wt%, for example, about 3-35 wt%, for example, about 4-15 wt%, for example, about 4-10 wt%. %, for example, about 3-15 wt.%, for example, about 3-10 wt.%, for example, about 3-6 wt.%, for example, about 3-5.5 wt.%, for example, about 4-6 mass%.

In another embodiment of the present invention, the rate controlling agent is present in an amount equal to 15-40 wt%, for example, about 15-25 wt%.

In another embodiment of the present invention, the rate controlling agent is present in an amount equal to 25-40 wt%, for example, about 35-40 wt%.

In another embodiment of the present invention, the rate controlling agent is present in an amount of 0-5 wt%, eg, about 0-3 wt%, for example, substantially no rate controlling agent.

In accordance with one aspect, the present invention relates to a pharmaceutical formulation comprising a degradable matrix that contains:

i) from 10 wt.% to 80 wt.%, for example from 20 wt.% to 70 wt.%, for example from 20 wt.% to 60 wt.%, for example from 30 wt.% to 60 wt. %, for example, from 35 wt.% to 60 wt.%, for example, from 35 wt.% to 55 wt.%, for example, from 40 wt.% to 55 wt.%, for example, from 40 wt.% to 50 wt%, for example 44 wt% to 55 wt%, for example 42 wt% to 48 wt% one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as an active substance; and

ii) from 0 wt.% to 40 wt.%, for example from 0 wt.% to 20 wt.%, for example from 0 wt.% to 10 wt.%, for example from 0 wt.% to 5 wt. %, for example, from 0 wt.% to 1 wt.%, one or more controlling the rate of agents;

the decomposition of the specified degradable matrix provides a controlled or delayed release of the specified active substance.

The amount, if present, of the rate controlling agent will vary depending on the particular rate controlling agent used, the targeted release characteristics, the level and nature of any excipients and additives present in the tablet core, etc.

In one embodiment of the present invention, the composition further comprises a binder. Non-limiting examples of said substance include water-soluble sugars and sugar alcohols such as lactose, sucrose, glucose, sorbitol, mannitol, etc. In one embodiment, the specified binder is lactose. Lactose is commercially available in a number of different grades depending on (including) the manufacturing method used, resulting in a range of particle sizes, particle size distribution, etc. Examples of lactose include, but are not limited to, anhydrous lactose, lactose derived from alpha-lactose monohydrate, agglomerated lactose, granular lactose, crystalline lactose, crystalline, sifted lactose (e.g., PrismaLac®, such as PrismaLac® 40) , crystalline, abrasive lactose (e.g. GranuLac®, such as GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLak® 230 and GranuLak® 400), improved lactose, agglomerated lactose (e.g. Tablettose® ®) such as Tablettoza® 70, Tablettoza® 80 and Tablettoza® 100), improved lactose, spray dried lactose (FlowLac®, such as FlowLac® 90 and FlowLac® 100). Lactose is available, for example, from Meggle Pharma under the trade names Prismolac®, Capsulac®, such as Capsulac® 60, SacheLac®, SpheroLac®, IngaLac®, Granulac® , such as GranuLak® 70, GranuLak® 140, GranuLak® 200, GranuLak® 230 and GranuLak® 400, SorboLac® (SorboLac®), Tablettoza® such as Tablettoza® 70, Tablettoza® 80 and Tablettoza® 100, FlowLac® ( FlowLac®) such as FlowLac® 90 and FlowLac® 100.

In one aspect, lactose is agglomerated lactose. In another aspect, lactose is spray dried lactose. In another aspect, lactose is abrasive lactose.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 40 wt.% to 60 wt.% one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 4-6 wt% rate control agent;

iii) 35-55 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 40 wt.% to 60 wt.% one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 15-50 wt% rate control agent;

iii) 5-30 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 30 wt.% to 60 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 35 wt.% to 55 wt.% one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 40-60 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 40 wt% to 50 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 45-55 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 42 wt.% to 48 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance;

ii) 3-5.5 wt% rate controlling agent;

iii) 45-52 wt% binder.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 30 wt.% to 60 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

iv) 0.15-0.7 wt% lubricant;

and optionally 0.05-0.25 wt% flow control agents.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 35 wt% to 55 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 40-60 wt% binder;

iv) 0.15-0.7 wt% lubricant;

and optionally 0.05-0.25 wt% flow control agents.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 40 wt% to 50 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or pharmaceutically an acceptable salt as an active substance;

ii) 3-6 wt% rate control agent;

iii) 45-55 wt% binder;

iv) 0.15-0.7 wt% lubricant;

and optionally 0.05-0.25 wt% flow control agents.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) from 42 wt.% to 48 wt.% of one or more esters of fumaric acid selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or their pharmaceutically an acceptable salt as an active substance;

ii) 3-5.5 wt% rate controlling agent;

iii) 45-52 wt% binder;

iv) 0.2-0.5 wt% lubricant;

and optionally 0.05-0.2 wt% flow control agents.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 30 wt% to 60 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 35-65 wt% lactose.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 35 wt% to 55 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 40-60 wt% lactose.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 40 wt% to 50 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 45-55 wt% lactose.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 42 wt% to 48 wt% dimethyl fumarate;

ii) 3-5.5 wt% HPC;

iii) 45-52 wt% lactose.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 30 wt% to 60 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 35-65 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate;

and possibly 0.05-0.25 wt% silicon dioxide.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 35 wt% to 55 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 40-60 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate;

and possibly 0.05-0.25 wt% silicon dioxide.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 40 wt% to 50 wt% dimethyl fumarate;

ii) 3-6 wt% HPC;

iii) 45-55 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate;

and possibly 0.05-0.25 wt% silicon dioxide.

In one embodiment of the present invention, the composition according to the present invention comprises:

i) 42 wt% to 48 wt% dimethyl fumarate;

ii) 3-5.5 wt% HPC;

iii) 45-52 wt% lactose;

iv) 0.2-0.5 wt% magnesium stearate;

and possibly 0.05-0.2 wt% silicon dioxide.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) the core of the tablet, consisting of:

i) from 30 to 60% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-5% of the particles are> 500 μm and 45-53% of the particles are> 250 μm, and 7-15% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 35-65 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) an enteric coating in an amount of about 1.5-3.5% by weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 35 to 55% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-5% of particles are> 500 μm and 45-53% of particles are> 250 μm, and 7-15% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 40-60 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 40 to 50% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-5% of particles are> 500 μm and 45-53% of particles are> 250 μm, and 7-15% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 45-55 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 42 to 48% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-5% of particles are> 500 μm and 45-53% of particles are> 250 μm, and 7-15% particles have a size <100 μm;

ii) 3-5.5 wt% HPC;

iii) 45-52 wt% lactose;

iv) 0.2-0.5 wt% magnesium stearate and 0.05-0.2 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 30 to 60% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-7% of the particles are> 500 μm and 42-59% of the particles are> 250 μm, and 3-12% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 35-65 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) The core of the tablet, consisting of:

i) 35 to 55% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-7% of particles are> 500 μm and 42-59% of particles are> 250 μm, and 3-12% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 40-60 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) an enteric coating in an amount of about 1.5-3.5% by weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 40 to 50% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-7% of particles are> 500 μm and 42-59% of particles are> 250 μm, and 3-12% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 45-55 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 42 to 48% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-7% of particles are> 500 μm and 42-59% of particles are> 250 μm, and 3-12% particles have a size <100 μm;

ii) 3-5.5 wt% HPC;

iii) 45-52 wt% lactose;

iv) 0.2-0.5 wt% magnesium stearate and 0.05-0.2 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) the core of the tablet, consisting of:

i) from 30 to 60% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-10% of the particles are> 500 μm and 40-65% of the particles are> 250 μm, and 2-10% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 35-65 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) an enteric coating in an amount of about 1.5-3.5% by weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 35 to 55% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-10% of the particles are> 500 μm and 40-65% of the particles are> 250 μm, and 2-10% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 40-60 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) a tablet core consisting of:

i) 40 to 50% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-10% of the particles are> 500 μm and 40-65% of the particles are> 250 μm, and 2-10% particles have a size <100 μm;

ii) 3-6 wt% HPC;

iii) 45-55 wt% lactose;

iv) 0.15-0.7 wt% magnesium stearate and 0.05-0.25 wt% silicon dioxide; and

B) enteric coating in an amount of about 1.5-3.5 wt.% Based on the weight of the specified core.

In one embodiment of the present invention, the composition according to the present invention comprises:

A) the core of the tablet, consisting of:

i) 42 to 48% by weight of dimethyl fumarate as an active substance having a particle size distribution such that 0-10% of particles are> 500 μm and 40-65% of particles are> 250 μm, and 2-10% particles have a size <100 μm;

ii) 3-5.5 wt% HPC;

iii) 45-52 wt% lactose;

iv) 0.2-0.5 wt% magnesium stearate and 0.05-0.2 wt% silicon dioxide; and

B) an enteric coating in an amount of about 1.5-3.5% by weight of the specified core.

In one embodiment, the composition of the present invention further comprises one or more lubricants.

In one embodiment, the composition of the present invention further comprises one or more flow control agents.

In one embodiment, the composition of the present invention further comprises one or more lubricants and one or more flow control agents.

In one embodiment, the composition of the present invention further comprises pharmaceutically acceptable fillers and additives selected from the group consisting of lubricants, glidants, disintegrants, flow control agents, solubilizers, pH adjusting agents, surfactants, and emulsifiers.

In one embodiment, the composition of the present invention is made without the use of a disintegrant.

Certain formulations of the present invention exhibit biphasic in vitro dissolution characteristics, with release of APIs such as dimethyl fumarate slower in acidic conditions in the first two hours in the USP dissolution apparatus, and faster once the dissolution medium is changed to pH 6.8 despite the fact that the solubility of the API can be the same in acidic and alkaline media. Thus, for drugs that require a relatively low gastric exposure but also require release / absorption in the small intestine, it will be possible to limit the effect of the API on the stomach while optimizing the effect of the API on the small intestine. In one embodiment, the in vitro dissolution characteristics of the composition are biphasic, i.e. the release of the API is slower in acidic conditions in the first two hours in the USP dissolution apparatus, and faster once the dissolution medium is changed to pH 6.8.

The in vitro dissolution rate describes how the released amount of API contained in a formulation of the present invention - when subjected to an in vitro dissolution test - changes over time. A higher / faster in vitro dissolution rate means that more API is released over a period of time, and a slower / slower in vitro dissolution rate means less API is released over the same time period - when exposed to the same dissolution test conditions in vitro.

In one embodiment of the present invention, an in vitro dissolution test used to determine the in vitro dissolution rate uses 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of the test, followed by 0.05 M phosphate buffer with pH 6.8 as dissolution medium.

In one embodiment of the present invention, the in vitro dissolution rate of the API contained in the uncoated enteric coated composition of the present invention when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium - higher in the indicated buffer (pH 6.8) phase compared to the acid phase (0.1 N hydrochloric acid as dissolution medium) in the dissolution test vitro, for example, at least 10% higher, for example, at least 20% higher, for example, at least 30% higher, for example, at least 40% higher, for example, at least 50% higher, for example, at least 60% higher, for example, at least 70% higher, for example, at least 80% higher, for example, at least 90% higher, for example, at least 100% higher, for example, at least 125% higher, for example, at least 150% higher, for example, at least 200% higher, for example, at least 250% higher, for example, at least 300% higher, for example, at least 350% higher, for example, at least 400% higher in the buffer (pH 6.8) phase compared to the acid phase (0.1 N hydrochloric acid as dissolution medium) in the in vitro dissolution test. In one embodiment, a comparison is made between the in vitro dissolution rate during the first hour of the test (between time = 0 and time = 1 hour) and the in vitro dissolution rate at 3 hours (between time = 2 hours and time = 3 hours) of the test. In another embodiment, a comparison is made between the in vitro dissolution rate during the first two hours of the test (between time = 0 and time = 2 hours) and the in vitro dissolution rate at 3 hours (between time = 2 hours and time = 3 hours) of the test. In another embodiment, a comparison is made between the in vitro dissolution rate during the first two hours of the test (between time = 0 and time = 2 hours) and the in vitro dissolution rate in the next 2 hours (between time = 2 hours and time = 4 hours) of the test. ... In another embodiment, a comparison is made between the in vitro dissolution rate during the first hour of the test (between time = 0 and time = 1 hour) and the in vitro dissolution rate between time = 2 hours and time = 2.5 hours of the test.

In one embodiment, the composition of the present invention further comprises one or more shells. In one embodiment of the present invention, said one or more coatings are added to improve the stability and swallowing characteristics of the tablets or to delay the release of the API. In one embodiment, said coatings are film coatings and / or enteric coatings. The film coating can improve swallowing performance as well as stability, and can also reduce the risk of sublimation of the active pharmaceutical ingredient. In addition, the film coating can improve the safety aspect of tablet handling. A film coating with an overlying enteric coating or an enteric coating itself may have similar advantages to those listed above for a film coating. However, in addition, the active pharmaceutical ingredient may not be released in the acidic environment of the stomach, which potentially protects the gastric mucosa from irritation if the API is irritating to the gastric mucosa.

In one embodiment of the present invention, said coating is an enteric coating.

Enteric coating agents can be selected from any of a variety of commercially available coating agents. Non-limiting examples of these substances include Eudragit® E, L, S, L30D55, Collicoat® 30D, cellulose acetate phthalate, polyvinyl acetate phthalate, and hypromellose phthalate.

In one embodiment of the present invention, said enteric coating is applied at a level of about 1.0-5.0% by weight of the core.

In one embodiment, the enteric coating is applied at a level of about 1.0-4.5% by weight of the core, such as 1.5-4.0% by weight of the core, such as about 1 , 5-3.5% by weight of the core, such as about 2.0-3.5% by weight of the core, such as about 2-3% by weight of the core.

In one embodiment of the present invention, said enteric coating is applied at a level of about 1.5-3.5% by weight of the core.

An enteric coating is a known approach for preventing or minimizing drug release in the stomach and providing release in the small intestine. These enteric polymer coatings operate on the principle of pH-dependent solubility: they are insoluble under conditions of low gastric pH, but soluble in the near-pH-neutral environment of the proximal small intestine, having a pH in the range of 5-6.

For drugs that require absorption in the small intestine, this leaves only a narrow "window" of release open, such as about 5 hours, such as about 4 hours, such as about 3 hours, such as about 2½ hours, such as about 2 hours between solubilization of the enteric coating and release of the API from the formulation. In some embodiments of the present invention, it has been found that rapid solubilization of the enteric coating is possible by applying a relatively thin coating while still unexpectedly obtaining the necessary protection against the acidic environment of the stomach, as, for example, shown when subjected to an in vitro dissolution test using 0, 1N hydrochloric acid as dissolution medium for 2 hours - less than 10%, for example, less than 5%, for example, less than 2%, for example, about 0% release of the fumaric acid ester contained in the composition.

In one embodiment of the present invention, the in vivo release of the fumaric acid ester exhibits an earlier onset of release than the prior art Fumaderm® formulation, e.g., at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes, at least 110 minutes, or at least 120 minutes earlier than Fumaderm® on an empty stomach.

In one embodiment of the present invention, the composition according to the present invention contains an enteric coating, and the release of the fumaric acid ester in vivo exhibits an earlier onset of release than the prior art Fumaderm® composition, for example, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes at least 110 minutes or at least 120 minutes earlier than Fumaderm® on an empty stomach.

In one embodiment of the present invention, the in vivo release of the fumaric acid ester exhibits a time difference of 15 minutes to 2 hours on an empty stomach, such as a time difference of no more than 120 minutes, no more than 10 minutes, no more than 100 minutes, no more than 90 minutes, no more than 80 minutes, no more than 70 minutes, no more than 60 minutes, no more than 50 minutes, no more than 40 minutes, no more than 30 minutes, no more than 20 minutes, or no more than 15 minutes on an empty stomach.

In one embodiment, the formulation of the present invention contains an enteric coating and the in vivo release of the fumaric acid ester exhibits a time difference of 15 minutes to 2 hours on an empty stomach, such as a time difference of no more than 120 minutes, no more than PO minutes, no more than 100 minutes, no more than 90 minutes, no more than 80 minutes, no more than 70 minutes, no more than 60 minutes, no more than 50 minutes, no more than 40 minutes, no more than 30 minutes, no more than 20 minutes or no more 15 minutes on an empty stomach.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 50 wt.% of the fumaric acid ester contained in the composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 3.5 hours after the start of the test, no more than about 95 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 4 hours after the start of the test, no more than about 98 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 60 wt.%, for example, from about 0 wt.% to about 50 wt.%, for example, from about 0 wt.% to about 40 wt. %, for example, from about 0 wt.% to about 30 wt.%, for example, from about 0 wt.% to about 20 wt.%, for example, from about 0 wt.% to about 10 wt.%, for example, from about 0 wt.% to about 5 wt.%, for example, about 0 wt.% fumaric acid ester contained in the composition, and / or

within the first 3 hours after the start of the test, from about 15 wt.% to about 95 wt.%, for example, from about 20 wt.% to about 95 wt.%, for example, from about 20 wt.% to about 75 wt. %, for example, from about 25 wt.% to about 75 wt.%, for example, from about 40 wt.% to about 95 wt.%, for example, from about 40 wt.% to about 75 wt.%, for example, from about 50 wt% to about 95 wt%, for example, from about 50 wt% to about 75 wt%, for example, from about 60 wt% to about 95 wt%, for example, from about 60 wt% to about 75 wt%, for example, from about 70 wt% to about 95 wt%, for example, from about 80 wt% to about 95 wt%, for example, from about 90 wt% to about 95 wt%. % of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 60 wt.% is released, for example from about 0 wt.% to about 5 wt.%, for example from about 0 wt.% to about 10 wt. %, or, for example, from about 15 wt.% to about 35 wt.%, or, for example, from about 35 wt.% to about 55 wt.% fumaric acid ester contained in the composition, and / or

during the first 3 hours after the start of the test, from about 15 wt.% to about 95 wt.%, for example, from about 15 wt.% to about 75 wt.%, for example, from about 20 wt.% to about 75 wt. %, for example, from about 15 wt.% to about 35 wt.%, or, for example, from about 35 wt.% to about 55 wt.%, or, for example, from about 55 wt.% to about 75 wt.% , or, for example, from about 65 wt.% to about 85 wt.%, or, for example, from about 70 wt.% to about 80 wt.%, or, for example, from about 75 wt.% to about 95 wt. %, or, for example, from about 85 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 1 wt.% to about 25 wt.% of the fumaric acid ester contained in the composition is released, and / or during the first 3 hours after the start of the test, from about 15 wt.% to about 95 are released wt%, for example, from about 15 wt% to about 75 wt%, for example, from about 25 wt% to about 95 wt%, for example, from about 25 wt% to about 75 wt%, for example , from about 40 wt% to about 95 wt%, for example, from about 40 wt% to about 75 wt%, for example, from about 50 wt% to about 95 wt%, for example, from about 50 wt% % to about 75 wt%, for example, from about 60 wt% to about 95 wt%, for example from about 60 wt% to about 75 wt%, for example, from about 70 wt% to about 95 wt% .%, for example, from about 80 wt.% to about 95 wt.%, for example, from about 90 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 1 wt.% to about 25 wt.% of the fumaric acid ester contained in the composition is released, and / or during the first 3 hours after the start of the test, from about 15 wt.% to about 95 are released wt%, for example, from about 15 wt% to about 75 wt%, for example, from about 15 wt% to about 35 wt%, or, for example, from about 35 wt% to about 55 wt% , or, for example, from about 55 wt.% to about 75 wt.%, or, for example, from about 65 wt.% to about 85 wt.%, or, for example, from about 70 wt.% to about 80 wt. %, or, for example, from about 75 wt.% to about 95 wt.%, or, for example, from about 85 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 3.5 hours after the start of the test, no more than about 100 wt% is released, for example, from about 30 wt% to about 100 wt%, for example from about 30 wt% to about 95 wt%, for example , from about 40 wt% to about 100 wt%, for example, from about 40 wt% to about 95 wt%, for example, from about 50 wt% to about 100 wt%, for example, from about 50 wt% % to about 95 wt%, for example, from about 60 wt% to about 100 wt%, for example, from about 60 wt% to about 95 wt%, for example from about 70 wt% to about 100 wt% .%, for example, from about 70 wt.% to about 95 wt.%, for example, from about 80 wt.% to about 100 wt.%, for example, from about 80 wt.% to about 95 wt.%, for example, from about 90 wt.% to about 100 wt.%, for example, from about 90 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 3.5 hours after the start of the test, no more than about 100 wt% is released, for example from about 30 wt% to about 90 wt%, for example from about 30 wt% to about 50 wt%, or , for example, from about 60 wt.% to about 80 wt.%, or, for example, from about 80 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 4 hours after the start of the test, no more than about 100 wt% is released, for example from about 35 wt% to about 100 wt%, for example from about 35 wt% to about 98 wt%, for example from about 40 wt% to about 100 wt%, for example, from about 40 wt% to about 98 wt%, for example, from about 50 wt% to about 100 wt%, for example from about 50 wt% to about 98 wt%, for example, from about 60 wt% to about 100 wt%, for example, from about 60 wt% to about 98 wt%, for example, from about 70 wt% to about 100 wt%. %, for example, from about 70 wt.% to about 98 wt.%, for example, from about 80 wt.% to about 100 wt.%, for example, from about 80 wt.% to about 98 wt.%, for example, from about 90 wt.% to about 100 wt.%, for example, from about 90 wt.% to about 98 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 4 hours after the start of the test, no more than about 100 wt% is released, for example from about 35 wt% to about 98 wt%, for example from about 50 wt% to about 70 wt%, or, for example , from about 85 wt.% to about 95 wt.% of the total amount of fumaric acid ester contained in the composition.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 4 hours after the start of the test, no more than about 95 wt%, for example, no more than about 90 wt%, for example, no more than about 70 wt% of the total fumaric acid ester contained in the formulation is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 15 wt.% to about 35 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 30 wt.% to about 50 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 50 wt.% to about 70 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 15 wt.% to about 35 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 30 wt.% to about 50 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 50 wt.% to about 70 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 30 wt.% to about 55 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 60 wt.% to about 80 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 80 wt.% to about 95 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 30 wt.% to about 55 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 60 wt.% to about 80 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 80 wt.% to about 95 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 5 hours after the start of the test, from about 80 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 60 wt.% to about 85 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 80 wt.% to about 95 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 85 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 60 wt.% to about 85 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 80 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 85 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 15 wt.% to about 35 wt.% of the fumaric acid ester contained in the composition is released, and during the first 3 hours after the start of the test, from about 55 wt.% to about 80 wt. % of the total amount of fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test, from about 70 wt.% to about 90 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 80 wt.% to about 100 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 10 wt.% to about 30 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 15 wt.% to about 40 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 30 wt.% to about 50 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 10 wt.% to about 30 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 15 wt.% to about 40 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 30 wt.% to about 50 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 6 hours after the start of the test, from about 75 wt.% to about 100 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 5 wt.% to about 25 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 10 wt.% to about 30 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 20 wt.% to about 40 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 5 wt.% to about 25 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 10 wt.% to about 30 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 20 wt.% to about 40 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 5 hours after the start of the test, from about 30 wt.% to about 50 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 2 wt.% to about 20 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 5 wt.% to about 20 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 5 wt.% to about 25 wt.% of the total amount of fumaric acid ester contained in the composition is released.

In one embodiment of the present invention, the release of the fumaric acid ester is when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium - proceeds as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to about 5 wt.% of the total amount of the fumaric acid ester contained in the composition is released, and

during the first 3 hours after the start of the test, from about 2 wt.% to about 20 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 3.5 hours after the start of the test, from about 5 wt.% to about 20 wt.% of the total amount of fumaric acid ester contained in the composition is released; and

during the first 4 hours after the start of the test, from about 5 wt.% to about 25 wt.% of the total amount of the fumaric acid ester contained in the composition is released; and

during the first 5 hours after the start of the test, from about 10 wt.% to about 30 wt.% of the total amount of the fumaric acid ester contained in the composition is released.

In one embodiment, the release has release kinetic characteristics of zero order, first order, or square root (Higuchi).

In another embodiment, the in vitro release has a combination of zero order, first order, and square root (Higuchi) release kinetic characteristics, eg, a combination of zero and first order in vitro release characteristics.

Various kinetic models such as zero order (1), first order (2), square root (Higuchi equation) (3) can be applied to explain the kinetics of drug release.

In these equations, M _t is the total amount of drug released at any given point in time, and M ₀ is the dose of the active substance included in the pharmaceutical composition, k ₀ , k _l and k _H are the rate constants for the zero equation order, first order, and Higuchi equation, respectively.

One aspect of the present invention relates to zero order dissolution release characteristics. Another aspect relates to the first order dissolution release characteristics. Another aspect relates to the dissolution release characteristics of the square root (Higuchi equation).

The active substance in the composition according to the present invention is any fumaric acid ester.

In one embodiment of the present invention, the fumaric acid ester is preferably selected from the group consisting of dimethyl fumarate, diethyl fumarate, dipropyl fumarate, dibutyl fumarate, dipentyl fumarate, methylethyl fumarate, methyl propyl fumarate, methyl butyl fumarate, methyl pentyl fumarate, monomethyl fumarate monoethyl fumarate, monoethyl fumarate mono substances.

Pharmaceutically acceptable salts of these substances include metal salts such as a salt selected from alkali metal salts and alkaline earth metal salts including sodium, potassium, calcium, magnesium, strontium or zinc salts, amino acid salts, etc.

In another embodiment of the present invention, the fumaric acid ester is present in the form of a monosaccharide ester, such as, for example, described in EP 06753340.6.

In another embodiment, the fumaric acid ester is in the form of an amino acid salt. The amino acid can be a naturally occurring amino acid such as glycine, alanine, valine, norvaline, isovaline, leucine, norleucine, isoleucine, methionine, phenylalanine, tryptophan, serine, threonine, cysteine, penicillamine, tyrosine, asparagine, glutamine, aspartic acid glutamic acid, ornithine, lysine, arginine, histidine, proline, 4-hydroxyproline, and pipicolinic acid.

In a specific embodiment of the present invention, the fumaric acid ester is a mono- (C ₁ -C ₅ ) -alkyl fumaric acid ester present in the form of a pharmaceutically acceptable salt. Suitable salts are, for example, metal salts such as a salt selected from alkali metal salts and alkaline earth metal salts including sodium, potassium, calcium, magnesium, strontium or zinc salt.

The term (C ₁ -C ₅ ) -alkyl refers to a branched or unbranched alkyl group of one to five carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2 -methyl-2-propyl, 2-methyl-1-propyl and pentyl.

In another embodiment, the composition according to the present invention contains dimethyl fumarate as the active substance.

In another embodiment, the composition according to the present invention contains monomethyl fumarate as an active substance, optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt.

In another embodiment, the composition according to the present invention contains monomethyl fumarate as the active substance, optionally in the form of an amino acid salt.

In another embodiment, the composition according to the present invention essentially consists of dimethyl fumarate as the active substance.

In another embodiment, the composition according to the present invention consists of dimethyl fumarate as the active substance.

In another embodiment, the composition according to the present invention essentially consists of monomethyl fumarate as an active substance, optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt.

In another embodiment, the composition according to the present invention consists of monomethyl fumarate as active agent, optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt.

In another embodiment, the composition according to the present invention contains dimethyl fumarate and monomethyl fumarate (optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt) as active substances in a weight ratio of about 1: 10 to about 10: 1.

In another embodiment, the composition according to the present invention essentially consists of dimethyl fumarate and monomethyl fumarate (optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt) as active substances in a weight ratio from about 1:10 to about 10: 1.

In another embodiment, the composition according to the present invention consists of dimethyl fumarate and monomethyl fumarate (optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium, strontium and / or zinc salt) as active substances in a weight ratio of from about 1 : 10 to about 10: 1.

In one embodiment, the composition of the present invention is intended to be administered once, twice, or three times a day.

In one embodiment, the composition is intended to be administered once a day.

In one embodiment, the composition is intended to be administered twice a day.

The daily dose of a controlled release pharmaceutical formulation of the present invention that is administered to treat a patient depends on a number of factors, including but not limited to weight and age, and the underlying cause of the condition or disease being treated, and is within the purview of the physician.

In accordance with one aspect of the present invention, the daily dose may be, for example, from 200 to 400 mg of active substance administered in one to three doses, in accordance with another aspect from 300 to 500 mg of active substance administered in one to three doses, in accordance with another aspect from 400 to 600 mg of active substance, administered in one to three doses, according to another aspect from 500 to 700 mg of active substance, administered in one to three doses, in accordance with another aspect from 600 to 800 mg active substance administered in one to three doses, in accordance with another aspect from 700 to 900 mg of active substance, administered in one to three doses, in accordance with another aspect from 800 to 1000 mg of active substance, administered in one to three doses, in accordance with another aspect from 900 to 1100 mg of active substance, administered in one to three doses, in accordance with another aspect from 1000 to 1200 mg of active substance, administered in one to three doses, in accordance with another aspect from 11 00 to 1300 mg of active substance, administered in one to three doses, in accordance with another aspect from 1200 to 1400 mg of active substance, administered in one to three doses, and according to another aspect, from 1300 to 2000 mg of active substance, administered in one to three doses.

One of the embodiments of the present invention is a pharmaceutical composition containing:

i) 40 wt% to 55 wt% dimethyl fumarate;

ii) 4-6 wt% hydroxypropyl cellulose;

iii) 35-55 wt% lactose.

One of the embodiments of the present invention is a pharmaceutical composition containing:

i) 30 wt% to 60 wt% dimethyl fumarate;

ii) 3-6 wt% hydroxypropyl cellulose;

iii) 35-65 wt% lactose.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a tablet with a degradable matrix, containing:

A) tablet core containing:

i) 40-60 wt.% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 4-6 wt% rate control agent;

iii) 35-55 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a tablet with a degradable matrix, containing:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, containing:

A) tablet core containing:

i) 40-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 4-6 wt% rate control agent;

iii) 35-55 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, containing:

A) tablet core containing:

i) 30-60 wt% of one or more fumaric acid esters selected from di- (C ₁ -C ₅ ) alkyl esters of fumaric acid and mono- (C ₁ -C ₅ ) alkyl esters of fumaric acid, or a pharmaceutically acceptable salt thereof as active substance,

ii) 3-6 wt% rate control agent;

iii) 35-65 wt% binder;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of the fumaric acid ester - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6.8 as dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of the fumaric acid ester contained in the specified composition is released.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a tablet with a degradable matrix, containing:

A) tablet core containing:

i) 40-55 wt% dimethyl fumarate,

ii) 4-6 wt% hydroxypropyl cellulose;

iii) 35-55 wt% lactose;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of dimethyl fumarate - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6 , 8 as a dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of dimethyl fumarate contained in the specified composition is released.

One of the embodiments of the present invention is a pharmaceutical composition in the form of a monolithic tablet with a degradable matrix, containing:

A) Tablet core containing:

i) 40-55 wt% dimethyl fumarate,

ii) 4-6 wt% hydroxypropyl cellulose;

iii) 35-55 wt% lactose;

B) enteric coating in an amount of about 1.5-3.5 wt.% By weight of the specified core;

the decomposition of said degradable matrix leads to the release of dimethyl fumarate - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as a dissolution medium during the first 2 hours of said test, and then 0.05 M phosphate buffer with pH 6 , 8 as a dissolution medium as follows:

during the first 2 hours after the start of the test, from about 0 wt.% to less than about 10 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 3 hours after the start of the test, from about 20 wt.% to about 75 wt.% of the dimethyl fumarate contained in the specified composition is released, and / or

during the first 4 hours after the start of the test, from about 50 wt.% to about 98 wt.% of the fumaric acid ester contained in the specified composition is released, and / or

during the first 5 hours after the start of the test, from about 70 wt.% to about 100 wt.% of the total amount of dimethyl fumarate contained in the specified composition is released.

The preparation of tablets with a degradable matrix according to the present invention can be carried out by granulation, followed by tabletting and optionally film and / or enteric coating of the resulting tablet cores. The core can be obtained, for example, by conventional wet granulation or continuous granulation such as extrusion followed by compacting the granules into tablets. The core can then be coated using a suitable technique, preferably by air suspension.

One aspect of the present invention is a method for preparing a composition according to the present invention, comprising the following steps:

a) Dissolving (or suspending) either one of or both the fumaric acid ester and possibly a rate controlling agent in the form of a polymeric matrix material in water to form an aqueous suspension of said materials;

b) Applying said aqueous suspension by spraying onto the fumaric acid ester and / or binder granules for a period of time sufficient to obtain a uniform coating thereon;

c) Drying the resulting granules;

d) Screening or grinding of said granules is possible;

e) Preparing a mixture with any pharmaceutically acceptable excipients and additives in a manner known per se to form a tablet formulation;

f) It is possible to film and / or enteric coatings on said tablet formulation in a manner known per se;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C. In one embodiment of the present invention, any or all of the above steps are performed at a temperature such that the product temperature does not exceed 40 ° C, for example, does not exceed 35 ° C, for example, does not exceed 30 ° C. Thus, it has surprisingly been shown that the preparation of the composition according to the present invention can be carried out using only water as solvent, thus eliminating the need for any organic solvents. Moreover, all the steps of the method can be carried out at a rather low temperature. In this way, any sublimation of the active pharmaceutical ingredient is minimized or reduced, and an energy-saving method is obtained that reduces the loss of API, thereby reducing the cost and also increasing the environmental safety and safety of workers.

In the present context, particle size is measured by conventional sieve analysis known to the person skilled in the art.

In one embodiment of the present invention, the fumaric acid ester is micronized to a particle size in which at least 90% of the particles are at most 50 microns, for example, not more than 30 microns, for example, not more than 10 microns, before step a) higher.

In another embodiment, the average particle size of the active pharmaceutical ingredient (ester (es) of fumaric acid) is reduced, for example, by sieving or milling, such that at least 50% of the particles are less than 800 microns, for example, less than 600 microns, for example, less 500 μm, for example less than 400 μm, for example less than 200 μm before step a) above.

In another embodiment, the average particle size of the active pharmaceutical ingredient (ester (es) of fumaric acid) is reduced, for example, by sieving or milling, such that at least 80% of the particles are less than 800 μm, for example, less than 600 μm, for example, less 500 μm, for example less than 400 μm, for example less than 200 μm before step a) above.

In another embodiment, the average particle size of the active pharmaceutical ingredient (ester (es) of fumaric acid) is reduced, for example, by sieving or milling, such that at least 90% of the particles are less than 800 μm, for example, less than 600 μm, for example, less 500 μm, for example less than 400 μm, for example less than 200 μm before step a) above.

In another embodiment, fumaric acid ester crystals are sieved or ground such that 90% of the particles are in the 5-1000 micron range, such as in the 10-900 micron range, such as in the 20-800 micron range, such as in the 30- 750 μm, such as in the range 40-600 μm, such as in the range 50-500 μm, such as in the range 100-400 μm, such as in the range 200-300 μm, such as in the range 300-600 μm, such as in the range of 300-400 μm, such as in the range of 400-600 μm, or such as in the range of 500-600 μm before step a) above.

In another embodiment, the average particle size of the active pharmaceutical ingredient (esters) of fumaric acid is in the range of 5-1000 microns, such as in the range of 10-900 microns, such as in the range of 20-800 microns, such as in the range of 30- 750 μm, such as in the range 40-600 μm, such as in the range 50-500 μm, such as in the range 100-400 μm, such as in the range 200-300 μm, such as in the range 300-600 μm, such as in the range of 300-400 μm, such as in the range of 400-600 μm, or such as in the range of 500-600 μm before step a) above.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (esters) of fumaric acid is such that 0-5% of the particles are> 500 μm and 45-53% of the particles are> 250 μm before step a) above ... In one embodiment, 7-15% of the particles are <100 μm before step a) above.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (esters) of fumaric acid is such that 0-7% of the particles are> 500 μm and 42-59% of the particles are> 250 μm, before step a) above ... In one embodiment, 3-12% of the particles are <100 μm before step a) above.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (ester (es) of fumaric acid) is such that 0-10% of the particles are> 500 μm and 40-65% of the particles are> 250 μm before step a) above ... In one embodiment, 2-10% of the particles are <100 μm before step a) above.

In one embodiment of the present invention, the average particle size of the active pharmaceutical ingredient (esters) of fumaric acid is reduced, for example, by sieving or milling, said sieving or milling being performed with minimal heat generation. In this way, any sublimation of the active pharmaceutical ingredient is minimized or reduced, and an energy-saving method is obtained that reduces the loss of API, thereby reducing the cost and also increasing the environmental safety and safety of workers. Screening or crushing can take place in one screening or crushing step, or it can be repeated several times to obtain the desired particle distribution. In one embodiment of the present invention, screening or grinding occurs in two stages. In one embodiment of the present invention, in which screening or grinding is performed in several stages, an agent to reduce agglomeration is added between these stages.

Without being bound by any particular theory, the present inventors believe that an active pharmaceutical ingredient (ester (es) of fumaric acid) having a particle size distribution in the above ranges leads to slower dissolution in vitro, and thus allows use a lower amount of rate controlling agent than a formulation having a large particle size distribution, for example such that more than 10% of the particles are> 500 μm and / or more than 65% of the particles are> 250 μm.

In one aspect, the lower amount of rate controlling agent allows a tablet to be produced with a high drug loading, such as at least 40%, 45%, 50%, 55%, or 60% of the active pharmaceutical ingredient based on the total weight of the tablet.

In one embodiment of the present invention, step b) is carried out in a fluidized bed granulator.

Another aspect of the present invention is a method for preparing a composition according to the present invention, comprising the following steps:

a) Dissolving (or suspending) the rate controlling agent in the form of a polymeric matrix material in water to form an aqueous suspension of said material;

b) Applying the specified aqueous suspension by spraying onto the fumaric acid ester granules for a period of time sufficient to obtain a uniform coating thereon;

c) Drying the resulting granules;

d) Screening or grinding of said granules is possible;

e) Preparing a mixture with any pharmaceutically acceptable excipients and additives in a manner known per se to form a tablet formulation;

f) Optionally, film coating and / or enteric coating of said tablet formulation in a manner known per se;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C. In one embodiment of the present invention, any or all of the above steps are performed at a temperature such that the product temperature does not exceed 40 ° C, for example, does not exceed 35 ° C, for example, does not exceed 30 ° C. In this way, any sublimation of the active pharmaceutical ingredient is minimized or reduced, and an energy-saving method is obtained that reduces the loss of API, thereby reducing the cost and also increasing the environmental safety and safety of workers.

In one embodiment of the present invention, the fumaric acid ester is micronized to a particle size in which at least 90% of the particles are at most 50 microns, such as at most 30 microns, such as at most 10 microns, before step b) above.

In another embodiment, the average particle size of the active pharmaceutical ingredient (ester (es) of fumaric acid) is reduced, for example, by sieving or milling, wherein at least 90% of the particles are at most 800 microns, such as at most 600 microns, such as not more than 500 microns, such as not more than 400 microns, such as not more than 200 microns before step b) above.

In one embodiment of the present invention, step b) is carried out in a fluidized bed granulator.

Another embodiment of the present invention is a method for preparing a composition according to the present invention, comprising the following steps:

a) Screening or crushing of fumaric acid ester crystals is possible;

b) Blending said fumaric acid ester crystals, optionally a rate controlling agent in the form of a polymeric matrix material, and any pharmaceutically acceptable excipients and additives by direct compression to form a tablet formulation;

c) Optionally, film coating and / or enteric coating of said tablet formulation in a substantially known manner;

wherein any or all of the above steps are carried out at a temperature such that the product temperature does not exceed 45 ° C. In one embodiment of the present invention, any or all of the above steps are performed at a temperature such that the product temperature does not exceed 40 ° C, for example, does not exceed 35 ° C, for example, does not exceed 30 ° C. In this way, any sublimation of the active pharmaceutical ingredient is minimized or reduced, and an energy-saving method is obtained that reduces the loss of API, thereby reducing the cost and also increasing the environmental safety and safety of workers.

Another embodiment of the present invention is a method for preparing a composition according to the present invention, comprising the following steps:

a) It is possible to sift or crush the crystals of the fumaric acid ester;

b) Mixing said fumaric acid ester crystals with any pharmaceutically acceptable excipients and optionally a rate controlling agent in the form of a polymeric matrix material in a manner known per se to form a tablet formulation;

c) Rolling this mixture and sieving / grinding it to obtain granules;

d) Preparation of a mixture of any additional pharmaceutically acceptable excipients with the specified granules to obtain a final mixture ready for tabletting;

e) Compression to obtain tablets;

О Possibly film and / or enteric coating of said tablets.

In one embodiment of the present invention, the fumaric acid ester is premixed with one or more pharmaceutically acceptable excipients prior to step a) above.

The stability of the formulations of the present invention can be determined by measuring the initial in vitro dissolution characteristics of the tablets and the in vitro dissolution characteristics after different storage periods and by comparing the in vitro dissolution characteristics obtained. In one embodiment, the tablets are stable for at least 6 months, such as at least 9 months, such as at least 12 months, such as at least 18 months, such as at least 24 months. according to the present invention can also be determined by standardized methods of measuring any changes, for example, in content, color or degradation products.

In one embodiment of the present invention, the stability of the formulation can be determined using objective criteria, such as, for example, the determined maximum change in the amount of API released at a predetermined time point in a standardized in vitro dissolution test when comparing the initial time of testing with testing at a later point in time. In one embodiment of the present invention, the amount of API released from the formulation stored under ICH conditions (e.g. 25 degrees C / 60% RH, e.g. 30 degrees C / 65% RH, e.g. 40 degrees C / 75% RH) in over a period of time (such as at least 1 month, such as at least 3 months, such as at least 6 months, such as at least 9 months, such as at least 12 months) compared to the starting point time (time = 0 set for stability testing) - when subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium for the first 2 hours of the specified test, and then 0.05 M phosphate buffer at pH 6.8 as a dissolution medium is as follows:

1 hour after the start of the test, a difference of less than 10 percentage points is observed, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point, in the amount of active pharmaceutical ingredient released from the composition, and / or

2 hours after the start of the test, a difference of less than 10 percentage points is observed, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point, in the amount of active pharmaceutical ingredient released from the composition, and / or

3 hours after starting the test, observe a difference of less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point, in the amount of active pharmaceutical ingredient released from the composition, and / or

4 hours after the start of the test, a difference of less than 10 percentage points is observed, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point, in the amount of active pharmaceutical ingredient released from the composition, and / or

5 hours after the start of the test, a difference of less than 10 percentage points is observed, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point, in the amount of active pharmaceutical ingredient released from the formulation.

In one embodiment, the pharmaceutical composition of the present invention is for use in the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, sclerotherapy, pemphigus vulgaris nerve pain, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplants (prevention of rejection), sarcoidosis, necrobiosis lipoidosis, or anular granuloma.

One embodiment is the use of a pharmaceutical composition according to the present invention for the preparation of a medicament for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uvectivitis, vernal sclerosus , optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidosis, or anular granuloma.

Another embodiment of the present invention is a method for treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidosis or anular granuloma, wherein said method comprises oral administration to a patient in need thereof, an effective dose of a pharmaceutical composition and according to the present invention.

In one embodiment, the composition of the present invention is for use in the treatment of psoriasis.

In one embodiment, the composition of the present invention is for use in the treatment of psoriatic arthritis.

In one embodiment, the composition of the present invention is for use in the treatment of multiple sclerosis or relapsing-remitting multiple sclerosis.

In one embodiment of the present invention, the composition of the present invention is for use in the treatment of rheumatoid arthritis.

It should be understood that the present invention is not limited to the specific embodiments described; these options can undoubtedly vary. It should also be understood that the terminology used in this description is given for the purpose of describing only specific implementations and is not limiting, since the scope of the present invention is limited only by the appended claims. If a range of values is given, it is understood that each intermediate value up to a tenth of a unit of the lower limit, unless the context clearly indicates otherwise, between the upper and lower limit of this range and any other specified or intermediate value in this specified range is included in the present invention ... The upper and lower bounds of these smaller ranges can be independently included in the smaller ranges, and are included in the present invention subject to any specifically excluded bounds in the indicated range. In the case where the specified range includes one or both boundaries, ranges excluding either one or both of these included boundaries are also included in the present invention. Unless otherwise defined, all technical and scientific terms used in this description have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. While any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention, preferred methods and materials are described. All publications mentioned in this document are incorporated herein by reference to disclose and describe the methods and / or substances in relation to which these publications are cited. It should be noted that, in the present description and the appended claims, the singular includes the plural, unless the context clearly indicates otherwise. The patents and publications mentioned in this document are provided solely for their description up to the filing date of this application. Nothing in this document can be construed as an admission that the present invention is not attributable to an earlier date of said patent or publication based on a prior invention. In addition, the dates of publication quoted may differ from the actual dates of publication, which may need to be independently confirmed. As is obvious to a person skilled in the art upon reading this description, each of the individual embodiments described and illustrated herein has discrete components and features that can be easily separated or combined with features of any of several other implementations within the scope. or the essence of the present invention. The figures described herein are not necessarily drawn to scale, with some components and features being exaggerated for clarity.

While the foregoing invention has been described in detail by way of illustrations and examples for a clear and complete understanding, it is obvious to one skilled in the art in light of the teachings of the present invention that some changes and modifications are possible within the spirit or scope of the appended claims.

EXAMPLES

During all of the following steps in Examples 1-24 and 26-42, the necessary precautions are taken (protective clothing with an external air source, double gloves, armbands, breathing mask, etc.).

Example 1

Obtaining tablet cores

540.5 g of finely divided dimethyl fumarate (average particle size 10 μm) and 31.5 g of HPC-SL hydroxypropyl cellulose were suspended in 1716 g of purified water. The slurry was sprayed for approximately 2 hours onto 405.5 g of GranuLac® 140 lactose placed in the basket of a fluid bed granulator. The granules were dried for 5 minutes. The protective coating was applied by spraying a solution of 22.5 g HPC-SL in 2265.5 g purified water over a period of approximately 2 hours. The product temperature never exceeded 35 ° C. Different batches were mixed and sieved through a 1.1 mm sieve.

183.3 g of dried sieved granules were mixed with 58.7 g of spray-dried lactose (FlowLac® 100) using a drum mixer at 30 rpm for 15 minutes. Finally, 2.4 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 10 mm in diameter and 375 mg in weight.

Example 2

Obtaining tablet cores

540.5 g of unmilled dimethyl fumarate and 405.5 g of GranuLac® 140 were placed in the basket of a fluidized bed granulator. 62.1 g of HPC-SL hydroxypropyl cellulose was dissolved by stirring in 3043 g of purified water and sprayed onto DMF for 2.5 hours. The granules were dried for 4 minutes at 29 ° C and sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

135 g of dried granules were mixed with 30.4 g of spray-dried lactose (FlowLac® 100), 24.4 g of HPC-SL and 0.3 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 1.8 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 10 mm in diameter and 315.5 mg in weight.

Example 3

Obtaining tablet cores

621.5 g of finely divided dimethyl fumarate (average particle size 500 μm) was suspended in 1793.5 g of purified water and stirred with an Ultra-turrax for 5 hours until the particle size was reduced. Then added 36.2 g of hydroxypropyl cellulose HPC-SL. The slurry was sprayed for approximately 2 hours onto 405.5 g of GranuLac® 140 placed in the basket of a fluidized bed granulator. The granules were dried for 5 minutes. Then, a protective coating obtained from 26.3 g of HPC-SL in 2605 g of purified water was applied by spraying the solution for about 2 hours on said granules. The product temperature never exceeded 30 ° C.

183.3 g of dried granules were mixed with 58.7 g of spray-dried lactose (FlowLac® 100) and 0.5 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 2.2 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 10 mm in diameter and 375.4 mg in weight.

Example 4

Obtaining tablet cores

1200 g of unmilled dimethyl fumarate was placed in the basket of a fluid bed granulator. 75 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring in 2925 g of purified water and sprayed on DMF for about 2.5 hours before spraying 70 g of HPC. The granules were dried for 4 minutes at 29 ° C and sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

378.2 g of dried granules were mixed with 400.6 g of spray-dried lactose (FlowLac® 100), 14.6 g of HPC-SL and 0.9 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 5.8 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight.

Example 5

Film coating of tablet cores according to example 4

Film coating

For film coating 800 g of tablet cores, a 15% Opadry suspension was prepared by adding 36 g of Opadry to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the tablet cores for 35 minutes in a fluidized bed chamber. The product temperature never exceeded 40 ° C. The coating process was followed by a drying period of 16 minutes at 30 ° C.

Example 6

Film and enteric coating of tablet cores according to example 4

Film coating

A film coat was applied to 800 g of tablet cores. Received a 15% suspension Opadra by adding 18 g Opadra to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the tablet cores for 20 minutes in a fluidized bed chamber. The product temperature never exceeded 40 ° C. The coating process was followed by a drying period of 9 minutes at 30 ° C.

Enteric coating

1 kg of gastric acid resistant coating liquid was prepared by heating 350 ml of purified water to 70-80 ° C, adding 20 g triethyl citrate, 3 g glyceryl monostearate (Cutina GMS V), 1 g Tween 80 (Tween 80) and stirring with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427.8 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 210 g of Eudragit L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating liquid was sprayed onto 780 g film-coated tablets in a fluidized bed chamber at 30 ° C for approximately 2.5 hours. This was followed by a drying period at 30 ° C for 30 minutes and a holding period at 35 ° C for another 30 minutes.

Example 7

Enteric Coating of Tablet Cores According to Example 4

Enteric coating

1 kg of gastric acid resistant coating fluid was prepared and sprayed onto the tablet cores as described in Example 6.

Example 8

Granules were prepared as described in Example 4.

416 g of dried granules were mixed with 360.8 g of spray-dried lactose (FlowLac® 100), 16 g of HPC-SL and 1 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 6.4 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Example 9

Film coating of tablet cores according to example 8

Film coating

Film coating was carried out as described in example 5.

Example 10

Film coating and enteric coating of tablet cores according to example 8

Film coating

Film coating was applied to 800 g of tablet cores as described in Example 6.

Enteric coating

1 kg of gastric acid resistant coating fluid was obtained and applied as described in Example 6.

Example 11

Granules were prepared as described in Example 4.

404.5 g of dried granules were mixed with 272.9 g of spray-dried lactose (FlowLac® 100), 15.5 g of HPC-SL and 0.9 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 6.2 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 12

Film coating of the tablet cores was carried out according to example 11.

Film coating

For film coating, 800 g of tablet cores were coated as described in Example 5. To obtain 800 g of tablets available for coating, the active tablets were mixed with a colored placebo.

Example 13

Film coating and enteric coating of tablet cores according to example 11.

Film coating

Film coating was applied to 800 g of tablet cores as described in Example 5. To obtain 800 g of tablets available for coating, the active tablets were mixed with a colored placebo.

Enteric coating

Received 1 kg of liquid for coating, resistant to gastric acid, and was applied as described in example 6.

Example 14

Granules were obtained as in example 4.

130 g of dried granules were mixed with 52.7 g of spray-dried lactose (FlowLac® 100), 40 g of HPC-SL and 0.3 g of Aerosil using a drum mixer at 30 rpm for 15 minutes. Finally, 2.0 g of magnesium stearate was added and mixed for another 10 minutes at 30 rpm. The final mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 15

Film coating of tablet cores according to example 14

Film coating

For film coating, 800 g of tablets were coated as described in Example 5. To obtain 800 g of tablets available for coating, the active tablets were mixed with a colored placebo.

Example 16

Film and enteric coating of tablet cores according to example 14

Film coating

A film coat was applied to 800 g of tablet cores. Therefore, the tablets containing the API were mixed with the colored placebo to obtain the required amount. Received a 15% suspension Opadrai and applied as described in example 6.

Enteric coating

1 kg of gastric acid resistant coating fluid was obtained and applied as described in Example 6.

The dissolution characteristics of the film-coated and enteric-coated tablets of this example were obtained according to the in vitro test of the United States Pharmacopoeia (USP). This test was carried out at 37 ° C. using a dissolution paddle at 100 rpm using 0.1 N hydrochloric acid as dissolution medium for the first 2 hours of the test, followed by 0.05 M phosphate buffer at pH 6. , 8 as dissolution medium for the remainder of the test. The result follows from FIG. one.

Example 17

1.2 kg of dimethyl fumarate was sieved through a 700 µm sieve and placed in the basket of a fluid bed granulator. 70.6 g of HPC-SL hydroxypropyl cellulose polymer was dissolved by stirring in 2753 g of purified water and sprayed on DMF for 2.5 to 3 hours. The granules were dried for 3 minutes at 29 ° C. Several batches were mixed and sieved through an 800 µm sieve.

1730.7 g of dried granules and additionally sifted through a 500 μm sieve were mixed with 781.3 g of granular lactose (Tablettoza® 100), 66.7 g of HPC-SL and a previously prepared mixture of Aerosil® and Tablettoza® using a drum mixer at 20 rpm / min for 15 minutes. The specified previously obtained mixture was prepared in a plastic bag of 4 g of colloidal silicic acid (Aerosil®) and 390.6 g of Tablettose®, and sieved through a 500 μm sieve. Finally, 26.7 g of magnesium stearate was added. The final mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 18

Film and enteric coating of tablet cores according to example 17

Film coating

For film coating 800 g of tablet cores, a 15% Opadrai suspension was prepared by adding 18 g Opadrai to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the tablet cores for 20 minutes in a fluidized bed chamber. The product temperature never exceeded 40 ° C. The coating process was followed by a drying period of 9 minutes at 30 ° C.

Enteric coating

1 kg gastric acid resistant coating fluid was prepared by heating 350 ml of purified water to 70-80 ° C, adding 9.5 g triethyl citrate, 1.9 g glyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427.8 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 210 g of Eudragit L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating fluid was sprayed onto 780 g film-coated tablets in a fluidized bed chamber.

The dissolution characteristics of the film-coated and enteric-coated tablets of this example were obtained according to an in vitro dissolution test as described in Example 16, using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test, and then 0 .05 M phosphate buffer pH 6.8 as dissolution medium. The result follows from FIG. one.

Example 19

1.2 kg of dimethyl fumarate was sieved through a 700 µm sieve and placed in the basket of a fluid bed granulator. 70.6 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring in 2753 g of purified water and sprayed on DMF for 2.5 to 3 hours. The granules were dried for 3 minutes at 29 ° C and sieved through a 500 µm sieve.

964 g of dried sieved granules were mixed with 565.5 g of granulated lactose (Tablettoza® 100), 37.4 g of HPC-SL and a previously prepared mixture of Aerosil® and Tablettoza® using a drum mixer at 20 rpm for 15 minutes. The specified previously obtained mixture was prepared in a plastic bag of 2.3 g of colloidal silicic acid (Aerosil®) and 282.7 g of Tablettose®, and also sieved through a 500 μm sieve. Finally, 14.9 g of magnesium stearate was added. The final mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Example 20

Film coating and enteric coating of tablet cores according to example 19

Film coating

For film coating 800 g of tablet cores, a 15% Opadrai suspension was prepared and applied as described in Example 18.

Enteric coating

1 kg gastric acid resistant coating fluid was prepared by heating 350 ml of purified water to 70-80 ° C, adding 9.5 g triethyl citrate, 1.9 g glyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427.8 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 210 g of Eudragit L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating liquid was sprayed onto 780 g film-coated tablets in a fluidized bed chamber at 30 ° C for approximately 2.5 hours. This was followed by a drying period at 30 ° C for 30 minutes and a holding period at 35 ° C for another 30 minutes.

The dissolution characteristics of the film-coated and enteric-coated tablets of this example were obtained according to an in vitro dissolution test as described in Example 16, using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test, and then 0 .05 M phosphate buffer pH 6.8 as dissolution medium. The result follows from FIG. one.

Example 21

1.2 kg of dimethyl fumarate was sieved through a 700 µm sieve and placed in the basket of a fluid bed granulator. 70.6 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring in 2753 g of purified water and sprayed on DMF for 2.5 to 3 hours. The granules were dried for 3 minutes at 29 ° C. Several batches were mixed and sieved through an 800 µm sieve.

1416 g of dried granules and additionally sifted through a 500 μm sieve were mixed with 1002.9 g of granular lactose (Tablettoza® 100), 54.6 g of HPC-SL and a previously prepared mixture of Aerosil® and Tablettoza® using a drum mixer at 20 rpm within 15 minutes. The specified previously obtained mixture was prepared in a plastic bag of 3.3 g of colloidal silicic acid (Aerosil®) and 501.4 g of Tablettose®, and sieved through a 500 μm sieve. Finally, 21.8 g of magnesium stearate was added. The final mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight.

Example 22

Film coating and enteric coating of tablet cores according to example 21

Film coating

For film coating 800 g of tablet cores, a 15% Opadrai suspension was prepared and applied as described in Example 18.

Enteric coating

1 kg gastric acid resistant coating fluid was prepared by heating 350 ml of purified water to 70-80 ° C, adding 9.5 g triethyl citrate, 1.9 g glyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427.8 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 210 g of Eudragit L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating liquid was sprayed onto 780 g film-coated tablets in a fluidized bed chamber at 30 ° C for approximately 2.5 hours. This was followed by a drying period at 30 ° C for 30 minutes and a holding period at 35 ° C for another 30 minutes.

The dissolution characteristics of the film-coated and enteric-coated tablets of this example were obtained according to an in vitro dissolution test as described in Example 16, using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test, and then 0 .05 M phosphate buffer pH 6.8 as dissolution medium. The result follows from FIG. one.

Example 23

Film coating of tablet cores according to example 18

Film coating

For film coating 800 g of tablet cores, a 15% Opadrai suspension was prepared by adding 36 g Opadrai to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the tablet cores for 35 minutes in a fluidized bed chamber. The product temperature never exceeded 40 ° C. The coating process was followed by a drying period of 16 minutes at 30 ° C.

Dissolution characteristics of film-coated tablets according to this example, subjected to an in vitro dissolution test using 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test, followed by 0.05 M phosphate buffer at pH 6.8 v as a dissolution medium follow from FIG. 2.

Example 24

18 g of pure DMF (particle size 250-500 μm) were mixed with 6.3 g HPC-SL, 9.1 g spray dried lactose (FlowLac® 100) and 0.045 g Aerosil. Finally, 0.3 g of magnesium stearate was added and mixed. The final mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 25

The study was a single-center study following an open, randomized, "inverted" design to investigate plasma concentrations, pharmacokinetics, safety and tolerability of pharmaceutical formulations of the present invention compared to the market-based Fumaderm® formulation as a reference. The tablets were administered as a single oral dose of 240 mg (2 tablets each containing 120 mg) at each treatment period according to randomization to 20 healthy Caucasian males. The study was divided into four treatment periods (Treatment Periods 1, 2, 3 and 4), which were separated by a "wash" period of at least 7 days.

Subjects were screened for suitability at least 21-2 days prior to first administration, including: checking inclusion / exclusion criteria; demographic information (including age, height, body weight, body mass index (BMI) and ethnicity); medical checkup; complete medical history; 12-lead electrocardiogram (ECG); the main indicators of the state of the body (blood pressure (BP), pulse rate (HR) and body temperature (TT)); clinical laboratory parameters (hematology, serum biochemistry and urinalysis); documentation of concomitant disease and drug therapy.

In each of the four treatment periods, subjects entered the study center on the evening of Day 1 and remained there until the 24-hour blood sample was collected for PK analysis and all safety measurements were taken (= Day 2 morning).

Subjects abstained from food in the evening. A single oral dose (two tablets) of one of the compositions of the present invention (Examples 18, 20 or 22) or two enteric-coated tablets of the reference drug Fumaderm®, each containing 120 mg of dimethyl fumarate (total dose of 240 mg of dimethyl fumarate), were administered Day 1 (according to randomization). The administration was given to subjects on an empty stomach together with 240 ml of tap water. A wash-off interval of at least 7 days was maintained between each administration.

The following assessments / measurements were carried out:

Blood sampling was performed to determine plasma concentrations and PK parameters before and at a pre-scheduled time after dosing.

Adverse events were documented in detail throughout the study.

Urine was collected before and at a pre-scheduled time after dosing.

Re-examination was performed at least 7 after the last injection (Treatment period 4), including: medical examination; main indicators of the state of the body (blood pressure, PE and TT); body weight; 12-lead ECG; clinical laboratory parameters (hematology, serum biochemistry and urinalysis); documentation of concomitant drug therapy and adverse events.

Example 26

Obtaining tablet cores

Dimethyl fumarate was sieved through a 500 μm hand sieve.

29.3 g of sieved dimethyl fumarate, 2.93 g of HPC-SL, 22.17 g of granular lactose (Tablettoza® 100), 0.07 g of Aerosil®, as well as 0.49 g of magnesium stearate were mixed for 10 minutes. The mixture was compressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 27a

Obtaining tablet cores

Dimethyl fumarate was sieved through a 500 μm hand sieve.

500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of spray dried lactose (FlowLac® 100) and 1.2 g of Aerosil® were mixed using a drum mixer for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 247 g of purified water to 70-80 ° C, then 9 g of triethyl citrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 495 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 200 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of solution sprayed onto the tablets was 1.5 wt% solids, which resulted in a 1% increase in the weight of the coated tablets compared to the tablet cores.

Example 27b

The preparation of tablet cores was carried out as described in Example 27a.

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 247 g of purified water to 70-80 ° C, then 9 g of triethyl citrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 495 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 200 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of solution sprayed onto the tablets was 2.5 wt% solids, resulting in a 1.8% increase in the weight of the coated tablets over the tablet cores.

Example 28

Obtaining tablet cores

Dimethyl fumarate was sieved through a 500 μm hand sieve.

500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of granular lactose (Tablettoza® 100) and 1.2 g of Aerosil® were mixed using a drum mixer for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 99 g of purified water to 70-80 ° C, then 10.1 g of triethyl citrate, 2.0 g of glyceryl monostearate (Cutina GMS V) and 0.8 g of Tween 80 , and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 198 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 224 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The solution was sprayed with an increase in the mass of the tablet cores by 3%.

Example 29a

Obtaining tablet cores

The dimethyl fumarate was ground with 1143 μm and 610 μm sieves.

500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of granular lactose (Tablettoza® 100) and 1.2 g of Aerosil® were mixed using a drum mixer for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 247 g of purified water to 70-80 ° C, then 9 g of triethyl citrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 495 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 200 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of Eudragit sprayed onto the tablets was 2.5 wt% solids, resulting in a 1.5% increase in the weight of the coated tablets compared to the tablet cores.

Example 29b

The preparation of tablet cores was carried out as described in Example 28a.

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 247 g of purified water to 70-80 ° C, then 9 g of triethyl citrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 495 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 200 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of Eudragit sprayed onto the tablets was 3.5 wt% solids, which resulted in a 2% increase in the weight of the coated tablets compared to the tablet cores.

Example 30

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was approximately 11%> 500 microns, approximately 70%> 250 microns and approximately 7% <100 microns. The average particle size was 358 microns.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The tablet cores were optionally enteric coated as described in Example 33a.

Example 31

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was approximately 3%> 500 μm, approximately 65%> 250 μm and approximately 6% <100 μm. The average particle size was 290 μm.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 32

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was approximately 3%> 500 μm, approximately 50%> 250 μm and approximately 10% <100 μm. The average particle size was 250 μm.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The tablet cores were optionally enteric coated as described in Example 33b.

Example 33a

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 1193 g of purified water to 70-80 ° C, then 45 g of triethyl citrate, 13.5 g of glyceryl monostearate (Cutina GMS V) and 5.4 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Was added 2385 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 1500 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of Eudragit sprayed onto the tablets was 3.0% by weight, resulting in an increase in the weight of the coated tablets as compared to the tablet cores by 2.5%.

Example 33b

Enteric coating

A gastric acid resistant coating fluid was prepared by heating 1193 g of purified water to 70-80 ° C, then 45 g of triethyl citrate, 13.5 g of glyceryl monostearate (Cutina GMS V) and 5.4 g of Tween 80 were added, and mixed with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Was added 2385 g of purified water and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. This emulsion was then slowly added to 1500 g of Eudragit L30 D 55 dispersion. The resulting gastric acid resistant coating liquid was sprayed onto the tablet cores directly in a perforated coating drum. The amount of Eudragit sprayed onto the tablets was 3.5%, resulting in a 3% increase in the weight of the coated tablets compared to the tablet cores.

Example 34

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was 8%> 500 μm, 80%> 250 μm and 0% <100 μm. The average particle size was 360 μm.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 35

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was 6%> 500 μm, 65%> 250 μm and 6% <100 μm. The average particle size was 305 μm.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 36

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added. The resulting particle size distribution was 3%> 500 μm, 63%> 250 μm and 6% <100 μm. The average particle size was 290 μm.

The crushed substance was additionally mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 37

Obtaining tablet cores

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. Before carrying out the second stage of grinding, 6 g of Aerosil® were added.

The crushed substance was additionally mixed with 240 g of HPC-SL and 1714 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg. The tablet cores can be enteric coated as described in example 33a or b.

Example 38

2500 g of dimethyl fumarate was ground by means of 1575 μm and 813 μm sieves. 240 g HPC-SL, 2.734 g Tablettose 100 and 6 g Aerosil® were added and mixed with DMF. The mixture was rolled and passed through a 1 mm sieve to obtain granules. 20 g of magnesium stearate was admixed to give the final mixture ready for tabletting. This mixture was compressed into tablets having a weight of 275 mg. The tablet cores can be enteric coated as described in example 33a or b.

Example 39

2500 g of DMF was mixed with 6 g of Aerosil® and then milled with 1575 μm and 813 μm sieves. Added 240 g HPC-SL, 2.734 g Tablettose 100 and, and mixed with DMF and Aerosil. The mixture was rolled and passed through a 1 mm sieve to obtain granules. 20 g of magnesium stearate was admixed to give the final mixture ready for tabletting. This mixture was compressed into tablets having a weight of 275 mg. The tablet cores can be enteric coated as described in Example 33a or b.

Example 40

2000 g of dimethyl fumarate was comminuted with 1575 μm and 813 μm sieves. 4.8 g of Aerosil® was added before carrying out the second grinding step.

475.3 g of the crushed substance was additionally mixed with 519.8 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 3.8 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 263 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 41

2000 g of dimethyl fumarate was comminuted with 1575 μm and 813 μm sieves. 4.8 g of Aerosil® was added before carrying out the second grinding step.

468.2 g of the crushed substance was additionally mixed with 15 g of HPC-SL and 512 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 3.7 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets with a diameter of 8 mm and a weight of 267 mg. The tablet cores can be enteric coated as described in example 33a or b.

Example 42

2000 g of dimethyl fumarate was comminuted with 1575 μm and 813 μm sieves. 4.8 g of Aerosil® was added before carrying out the second grinding step.

500 g of the crushed substance was additionally mixed with 32 g of HPC-SL and 562.8 g of granular lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was added and the mixture was mixed again for 10 minutes at 20 rpm. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight. The tablet cores can be enteric coated as described in example 33a or b.

Example 43

A study such as described in Example 25 was carried out using the tablets described in Examples 18 and 22 and compared with corresponding data for the prior art Fumaderm formulation. The results of this study are shown in Table I and Table II below.

The above results of the clinical study (Table II) show that the tested formulations have a markedly reduced incidence of adverse effects combined with lower variability (see Table 1) compared to Fumaderm®. Thus, this example demonstrates that the formulations of the present invention exhibit an unexpectedly strong reduction in the AUC variability and C _max compared to the prior art Fumaderm® formulation.

Claims (27)

1. A pharmaceutical composition in the form of a tablet with a degradable matrix, containing: 1) a kernel containing: i) 35 to 55% by weight of a dimethyl fumarate core as an active substance; ii) 3 to 6% by weight of the core of the rate control agent, which is hydroxypropyl cellulose; iii) from 40 to 60% by weight of the binder core, which is lactose; iv) from 0.15 to 0.7% by weight of the core lubricant, which is magnesium stearate; and v) 0.05 to 0.25% by weight of the core of the flow control agent, which is silicon dioxide; and 2) enteric coating, where the specified enteric coating is applied at a level of from 1.5 to 3.5% by weight of the core. 2. The pharmaceutical composition of claim 1, wherein the degradable matrix tablet is a monolithic degradable matrix tablet. 3. The pharmaceutical composition according to any one of paragraphs. 1, 2 for use in the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain, associated root with radiculopathy, neuropathic pain or sciatica / sciatica pain, rejection after organ transplantation, sarcoidosis, necrobiosis lipoidosis, or anular granuloma. 4. The use of a pharmaceutical composition according to any one of claims. 1, 2 for obtaining a drug for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus ), Sjogren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, pemphigus vulgaris, scleroderma, or organ transplant rejection. 5. Use according to claim 4 for preparing a medicament for the treatment of psoriasis. 6. Use according to claim 4 for the preparation of a medicament for the treatment of psoriatic arthritis. 7. Use according to claim 4 for producing a medicament for the treatment of multiple sclerosis. 8. Use according to claim 4 for preparing a medicament for the treatment of rheumatoid arthritis. 9. The use of a pharmaceutical composition according to any one of paragraphs. 1, 2 for obtaining a drug for the treatment of myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis or optic neuritis. 10. The use of a pharmaceutical composition according to any one of claims. 1, 2 for preparing a medicament for the treatment of pain, radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain. 11. The use of a pharmaceutical composition according to any one of claims. 1, 2 for the preparation of a drug for the treatment of sarcoidosis, necrobiosis lipoidosis or anular granuloma. 12. A method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, pemphigus vulgaris, scleroderma, rejection after organ transplantation, including oral administration to a patient in need of it, an effective dose of the pharmaceutical composition according to any one of paragraphs. 12. 13. The method of claim 12 for treating psoriasis. 14. The method of claim 12 for the treatment of psoriatic arthritis. 15. The method of claim 12 for treating multiple sclerosis. 16. The method of claim 12 for treating rheumatoid arthritis. 17. A method of treating myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis or optic neuritis, including oral administration to a patient in need thereof, an effective dose of the pharmaceutical composition according to any one of paragraphs. 12. 18. A method of treating pain, radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica / sciatica pain, comprising oral administration to a patient in need thereof, an effective dose of the pharmaceutical composition according to any one of claims. 12. 19. A method of treating sarcoidosis, necrobiosis lipoidosis or anular granuloma, comprising oral administration to a patient in need thereof, an effective dose of the pharmaceutical composition according to any one of claims. 12.

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